Dextromethorphan transdermal delivery device

ABSTRACT

Provided herein are transdermal delivery devices comprising dextromethorphan. The transdermal delivery device can be characterized by the novel design, for example, with an adhesive layer and a reservoir layer, with an adhesive layer comprising a mixture of two adhesives, and/or with a skin permeation enhancer, e.g., in an amount that can significantly enhance the flux of dextromethorphan. The transdermal delivery device can also be characterized by its in vitro and/or in vivo release profile, for example, that can provide a desired pharmacokinetic profile described herein. Also provided herein are methods of administering dextromethorphan, and methods of treating a disease or disorder described herein, using the transdermal delivery device herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase of International ApplicationNo. PCT/US2018/054178 filed Oct. 3, 2018 which designated the U.S. andclaims priority to U.S. Provisional Application Nos. 62/568,028, filedOct. 4, 2017, and 62/680,182, filed Jun. 4, 2018, the entire contents ofeach of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION Field of the Invention

In various embodiments, the present invention generally relates totransdermal delivery devices comprising dextromethorphan, and methods ofpreparing and uses thereof, for example, for use in treating a diseaseor disorder such as a neurological disease.

Background Art

NUEDEXTA® (dextromethorphan hydrobromide and quinidine sulfate)capsules, 20 mg/10 mg is a combination product containingdextromethorphan hydrobromide (an uncompetitive N-methyl-D-aspartate[NMDA] receptor antagonist and sigma-1 agonist) and quinidine sulfate (aCYP450 2D6 inhibitor). This product is indicated for the treatment ofpseudobulbar affect (PBA). Dextromethorphan hydrobromide is thepharmacologically active ingredient of NUEDEXTA® that acts on thecentral nervous system (CNS). Quinidine sulfate is a specific inhibitorof CYP2D6-dependent oxidative metabolism used in NUEDEXTA® to increasethe systemic bioavailability of dextromethorphan.

The recommended starting dose of NUEDEXTA® (dextromethorphanhydrobromide and quinidine sulfate) capsules, 20 mg/10 mg is one capsuledaily by mouth for the initial seven days of therapy. On the eighth dayof therapy and thereafter, the daily dose should be a one capsule every12 hours for a total of two capsules daily. The need for continuedtreatment should be reassessed periodically, as spontaneous improvementof PBA occurs in some patients.

The most common adverse reactions (incidence of ≥3% and two-fold greaterthan placebo) in patients taking NUEDEXTA® in descending order arediarrhea, dizziness, cough, vomiting, asthenia, peripheral edema,urinary tract infection, influenza, increased gamma glutamyltransferase,and flatulence. The following adverse reactions have been reported withthe use of the individual component dextromethorphan: drowsiness,dizziness, nervousness or restlessness, nausea, vomiting, and stomachpain.

BRIEF SUMMARY OF THE INVENTION

In various embodiments, the present invention is directed to noveltransdermal delivery devices comprising dextromethorphan, pharmaceuticalcompositions comprising dextromethorphan, and methods of administeringdextromethorphan transdermally. The transdermal delivery devices,pharmaceutical compositions, and methods herein are useful in treatingvarious diseases and disorders such as neurological diseases ordisorders (e.g., PBA).

The transdermal delivery devices herein are novel in various aspects. Insome embodiments, the transdermal delivery device can be characterizedby a patch design, for example, having an adhesive layer and a reservoirlayer. Typically, the reservoir layer can comprise a concentration ofdextromethorphan at least 10% by weight of the reservoir layer. In someembodiments, the transdermal delivery device can be characterized by anadhesive layer comprising a mixture of two adhesives, such as a mixtureof an acrylate adhesive and a silicone adhesive. In some embodiments,the transdermal delivery device can be characterized by having a skinpermeation enhancer, for example, that can provide a higher fluxcompared to an otherwise equivalent transdermal delivery device withoutthe skin permeation enhancer. In some embodiments, the transdermaldelivery device can be characterized by having certain specific releaseprofiles, such as in vitro flux profiles when tested using human cadaverskin and/or in vivo release profiles. In any of the embodimentsdescribed herein, the transdermal delivery device can be configured toprovide one or more in vitro release profile and/or one or more PKprofiles described herein in a user. In some embodiments, thetransdermal delivery device can provide a pharmacokinetic (“PK”) profilewith a pharmaceutically effective plasma concentration ofdextromethorphan in a subject in need thereof (e.g., subject having PBA)for a desired period of time. In some embodiments, the transdermaldelivery device can be configured for use once daily, e.g., to provide adaily dose of dextromethorphan about 2 mg to about 50 mg. In someembodiments, the transdermal delivery device can be configured for useonce in at least one day, for example, once in two days or more (e.g.,once a week), or 1, 2, 3, 4, 5, or 6 times a week, e.g., to provide adaily dose of dextromethorphan about 2 mg to about 50 mg. Any of thesefeatures/aspects can be combined with the others and such combinationsare specifically contemplated by the present disclosure.

In some embodiments, the transdermal delivery device can comprise anadhesive layer comprising an adhesive, which optionally comprisesdextromethorphan dispersed in the adhesive in an amount of about 2% toabout 12% by weight of the adhesive layer; and a reservoir layercomprising dextromethorphan in an amount of at least 10% (e.g., about20% to about 60%) by weight of the reservoir layer. In some embodiments,the transdermal delivery device can comprise an adhesive layercomprising dextromethorphan dispersed in an adhesive comprising anacrylate adhesive and a silicone adhesive, wherein the weight ratio ofthe acrylate adhesive to silicon adhesive can range for example fromabout 20:1 to about 1:20. In some embodiments, the transdermal deliverydevice can comprise an adhesive layer comprising dextromethorphandispersed in an adhesive, wherein the adhesive layer comprises a skinpermeation enhancer, for example, in an amount to provide a meancumulative dextromethorphan permeated at 24 hours post application of atleast about 25% (e.g., about 25%, about 50%, about 100%, about 150%,about 200%, or any ranges between the recited value) higher than that ofan otherwise equivalent transdermal delivery device without the skinpermeation enhancer, when tested in vitro using human cadaver skin.

In some embodiments, the present disclosure provides a method ofadministering dextromethorphan to a subject (e.g., human subject) inneed thereof. In some embodiments, the method comprises applying atransdermal delivery device to the skin of the subject. In someembodiments, the applying results in one or more PK profiles describedherein. In some embodiments, the transdermal delivery device isconfigured to have a flux characteristic such that the applyingtransdermally delivers dextromethorphan about 2 mg/day to about 50mg/day to the subject. In some embodiments, the transdermal deliverydevice comprises an adhesive layer, wherein the adhesive layer comprisesdextromethorphan dispersed in an adhesive, and a skin permeationenhancer, wherein the skin permeation enhancer is in an amount such thatthe applying results in a mean cumulative dextromethorphan permeated at24 hours post application of at least about 25% (e.g., about 25%, about50%, about 100%, about 150%, about 200%, or any ranges between therecited value) higher than that from applying an otherwise equivalenttransdermal delivery device without the skin permeation enhancer. Insome embodiments, the transdermal delivery device is applied once daily.In some embodiments, the transdermal delivery device is applied once inat least one day, e.g., once a week, twice a week, or three times aweek.

In some embodiments, the present disclosure provides a method oftreating a disease or disorder (e.g., a neurological disease or disordersuch as PBA) in a subject (e.g., human subject) in need thereof. In someembodiments, the method comprising applying a transdermal deliverydevice comprising dextromethorphan to the skin of the subject, whereinthe applying results in one or more of the PK profile described herein.In some embodiments, the transdermal delivery device is applied oncedaily. In some embodiments, the transdermal delivery device is appliedonce in at least one day, e.g., once a week, twice a week, or threetimes a week.

The methods herein are not limited to a particular subject or aparticular class of subjects. In some embodiments, the subject ischaracterized as an extensive metabolizer. In some embodiments, thesubject is characterized as a poor metabolizer. In some embodiments, thesubject is not co-administered a CYP2D6 inhibitor. In some embodiments,the subject is not co-administered quinidine. In some embodiments, thesubject is co-administered a CYP2D6 inhibitor such as quinidine,bupropion, etc. However, in any of the embodiments described herein, thesubject does not suffer from a cough and/or does not need anantitussive.

In some embodiments, the methods herein can further compriseadministering to the subject an active agent other thandextromethorphan. For example, in some embodiments, the method comprisesadministering to the subject an antidepressant. In some embodiments, themethod described herein further comprises administering to the subjectone or more additional active agents selected from amlodipine, acapsaicinoid (e.g., capsaicin or an ester thereof), an opioid agonist(e.g., a μ-opiate analgesic (e.g., tramadol)), an adenosinergic agonist,3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, andpharmaceutically acceptable salts thereof. These additional agents canbe administered simultaneously or sequentially, via the same ordifferent route.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 presents graphs showing in vitro flux study results fortransdermal delivery device with Formulations A and B with differentadhesives, the flux of dextromethorphan (DXM) from the patch withFormulation A (acrylate adhesive) is shown on the top with a faster fluxthan the patch with Formulation B (silicone adhesive).

FIG. 2 presents graphs showing in vitro flux study results for patcheswith Formulations C1-C3, which contains different ratios of siliconeadhesive to acrylic adhesive, 54:46 (middle), 18:92 (bottom), and 9:91(top).

FIG. 3 presents graphs showing effects of a skin permeation enhancer(isopropyl myristate, IPM) on in vitro flux: 10% IPM (top), 7.7% IPM(middle), and 0% IPM (bottom).

FIG. 4A shows dextromethorphan plasma concentration over the course of96 hours for a human clinical study comparing the effect ofadministration of DXM transdermal patch (test A) for 24 hours and oraladministration of Neudexta (20 mg DXM/10 mg quinidine) (Reference B)twice a day. FIG. 4B shows the metabolite, dextrorphan's plasmaconcentration over the course of 96 hours for the same study. For FIGS.4A and 4B, both test and reference administration were to subject underfasted condition. The plasma concentrations refer to mean plasmaconcentrations, with N=16.

FIG. 5 shows a multilayer patch design. The top layer is askin-contacting adhesive layer, the middle layer is a reservoir layer,and the bottom layer is a backing layer or an adhesive layer, which canbe the same or different from the top layer.

FIGS. 6A and 6B show simulated plasma concentrations of dextromethorphanover time following administration of DXM transdermal patches, 45 cm²(FIG. 6A), 60 cm² (FIG. 6B), or 90 cm² patch (FIG. 6B), once daily for 7days. The plasma concentrations of dextromethorphan (DM) over timefollowing oral administration of Neudexta (20 mg DXM/10 mg quinidine)twice a day for 7 days are also shown for comparison.

FIGS. 6C and 6D show simulated plasma concentrations of dextrorphan(Dor) over time following administration of DXM transdermal patches, 45cm² (FIG. 6C), 60 cm² (FIG. 6D), or 90 cm² patch (FIG. 6D), once dailyfor 7 days. The plasma concentrations of dextrorphan over time followingoral administration of Neudexta (20 mg DXM/10 mg quinidine) twice a dayfor 7 days are also shown for comparison.

FIG. 7 shows a two-zone patch design.

DETAILED DESCRIPTION OF THE INVENTION

The unpredictability of transdermal administration is notorious. In theinventor's experience, testosterone can be delivered transdermallywithout enhancer at a rate three orders of magnitude higher than forbeta estradiol. Structurally and by calculated Log P, these compoundsare very similar, such that this difference could not be anticipated.See, U.S. Provisional Appl. No. 62/568,028, filed Oct. 4, 2017, thecontent of which is incorporated by reference in its entirety.

Dextromethorphan (DXM) has been used orally to treat neurologicaldisorders such as pseudobulbar affect (PBA), emotional lability,agitation in Alzheimer's, major depressive disorder, treatment resistantdisorder, pain management, other CNS disorders, and the like. But, to beeffective, it must be delivered with a substance that competitivelyinhibits the liver enzyme cytochrome P450 2D6 (CYP2D6). It particular,this has meant it is co-administered with quinidine. Otherwise, toolittle makes it pass the liver's diligence of digested food. U.S. Pat.No. 6,335,030 B1 describes some examples of dextromethorphan patches. Nopharmacokinetic data on transdermal administration of dextromethorphanwas known.

As detailed herein, the present disclosure first shows thatdextromethorphan can be delivered transdermally in a therapeuticallyeffective amount. Transdermally delivering dextromethorphan can beadvantageous in many different aspects. For example, because thetransdermal route avoids first-pass metabolism, the transdermal deliverydevices herein can be administered to achieve therapeutically effectiveplasma concentration without regard to whether a CYP2D6 inhibitor suchas quinidine is co-administered. As such, the transdermal deliverydevice and methods herein can be administered to transdermally deliverdextromethorphan to subjects who are for example, sensitive orintolerant to CYP2D6 inhibitors such as quinine (e.g., having one ormore side effects associated with quinidine, or is co-administered adrug whose metabolism is affected by CYP2D6 inhibitors such asquinidine). Further, the transdermal delivery device and methods hereincan be conveniently administered to transdermally deliverdextromethorphan to a subject without regard to, e.g., with/withoutfirst determining, whether the subject is a poor metabolizer, anintermediate metabolizer, or an extensive metabolizer ofdextromethorphan. For brevity, as used herein, unless otherwise obviousfrom context, poor metabolizer (PM), intermediate metabolizer (IM), orextensive metabolizer (EM) refers to the subject's ability to metabolizedextromethorphan. Categorization of a subject as a PM, IM, or EM(alternatively labeled as ultrametabolizers or ultrarapid metabolizersor UM) is known in the art. See e.g., Treducu A. L. D. et al. Frontiersin Pharmacology, vol. 9, Article 305 (April 2018), which based ongenotype assigned subjects as UM if containing “≥3 normal function genecopies”).

Further, unexpectedly, administering the transdermal delivery devicesherein can provide a longer T_(1/2) of dextromethorphan, a reducedamount of metabolite (evidenced by the higher ratio of dextromethorphanto dextrophan), and/or a lower peak to trough ratio, when compared tothe corresponding parameters observed from oral administration ofNeudexta. These characteristics can provide superior clinical experiencecompared to Neudexta, for example, with more accurate dosing, lessfrequent dosing, and reduced potential for side effects. The transdermaldelivery devices herein can also be configured as a one day patch, 2-daypatch, 3-day patch, 4-day patch, 5-day patch, 6-day patch, or 7-daypatch, which is suitable for dosing frequencies ranging from once a dayto once a week, for example, once in more than 24 hours, more than 36hours, more than 48 hours, etc., or 1, 2, 3, 4, 5, or 6 times a week.Thus, using the transdermal delivery devices herein can provide improvedpatient compliance, at least by avoiding the twice-a-day dosing regimenof Neudexta.

Transdermal Delivery Device Comprising Dextromethorphan

Certain embodiments of the present disclosure are directed to noveltransdermal delivery devices comprising dextromethorphan.

Various patch designs can be used for the transdermal delivery deviceherein. The transdermal delivery device herein typically comprises abacking layer, an adhesive layer (e.g., a drug-in-adhesive layer), whichis the skin-contacting layer when in use, and optionally a reservoirlayer. The adhesive layer typically comprises dextromethorphan dispersed(e.g., homogenously dispersed, which also includes dissolved) in anadhesive, preferably a pressure sensitive adhesive. More than oneadhesive layers can be used for the transdermal delivery device herein.The adhesive layer is typically formulated such that the transdermaldelivery device can adhere to the skin of a user for a desired period oftime. For example, in some embodiments, the transdermal delivery deviceis capable of adhering continuously to the skin of a user for about 8hours, about 12 hours, about 18 hours, about 24 hours, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, or about 7 daysor more.

In some embodiments, the transdermal delivery device can be adrug-in-adhesive (DIA) patch. In some embodiments, the DIA patch is asingle layer patch, for example, the single layer includesdextromethorphan homogenously dispersed in the adhesive. In someembodiments, the DIA patch is a multilayer patch. For example, twodrug-in-adhesive layers can be included in the patch, which isoptionally separated by a membrane, e.g., a rate-controlling membrane,or by a reservoir layer. In some embodiments, one of thedrug-in-adhesive layer can be a reservoir layer, for example, with ahigher dextromethorphan concentration than the other layer. In someembodiments, the two drug-in-adhesive layers can sandwich a reservoirlayer.

A drug-in-reservoir (DIR) design can also be used for the transdermaldelivery device herein. In some embodiments, the reservoir layer and theadhesive layer can be laminated to each other or separated, for example,by a rate-controlling membrane. For example, in some embodiments, thereservoir layer, such as a drug matrix, can be laminated with theadhesive layer. Those skilled in the art would understand that suchadhesive layer can also contain certain amount of drug, for example,through equilibrium.

Other patch designs can also be used for the transdermal delivery deviceherein. For example, in some embodiments, the transdermal deliverydevice can be an active patch, such as an iontophoresis patch. In someembodiments, the transdermal delivery device can be a minimally invasivepatch, such as a microneedle based patch.

The transdermal delivery device can include dextromethorphan as the onlydrug or in combination with another drug. Unless obviouslycontradictory, in any of the embodiments described herein,dextromethorphan can be the only drug in the transdermal deliverydevice. Dextromethorphan can exist in various forms, for example, as afree base or a pharmaceutically acceptable salt. As used herein, theweight percentage, concentration, flux, etc. regarding dextromethorphanshould be understood as the total amount of dextromethorphan measuredand/or calculated, with the value expressed in the equivalent value fordextromethorphan base. Further, all weight percentages, unless otherwiseobvious from context, should refer to the weight percentage based on thefinal formulation (e.g., final adhesive layer or reservoir layer etc.)or transdermal delivery device as appropriate. In any of the embodimentsdescribed herein, the dextromethorphan can exist in its free base form,except that it can be protonated through equilibrium with otheringredient(s). For example, in any of the embodiments described herein,the transdermal delivery device or pharmaceutical compositions describedherein can be prepared by mixing directly or indirectly the recitedamount of dextromethorphan base with the other ingredients.

In any of the embodiments described herein, the dextromethorphan in thetransdermal delivery device can be partially or completely replaced witha deuterated dextromethorphan, e.g., the d3 analog (O-CD₃, or N-CD₃) ord6 analog (N-CD₃,O-CD₃) see, e.g., claims 1 and 17 of U.S. Pat. No.7,973,049, the content of which is incorporated by reference in itsentirety. Apparently, in such embodiments, the methods using thedeuterated dextromethorphan patches would provide deuterateddextromethorphan to the user. As used herein, a deuterateddextromethorphan refers to a compound resulted from substituting one ormore hydrogen atoms of dextromethorphan with deuterium such that eachsubstituted position has a deuterium content above the naturalabundance, i.e., the substituted position is enriched with deuterium. Insome embodiments, the deuterated dextromethorphan has at least oneposition with deuterium enriched to at least 10% deuterium, at least 50%deuterium, at least 90% deuterium, at least 95% deuterium or at least98% deuterium. In any of the embodiments described herein, thedextromethorphan in the transdermal delivery device can also bepartially or completely replaced with a dextromethorphan analog, such asa fluorinated dextromethorphan or a skin permeable prodrug ofdextromethorphan, etc.

The adhesive layer typically includes a pressure sensitive adhesive(PSA). Useful features for pressure sensitive adhesive include adequatetack, good adhesion and cohesive strength. Further useful attributesinclude biocompatibility (e.g., non-irritating, non-sensitizingnon-toxic), formulation compatibility, delivery system compatibility andthe like. Useful pressure sensitive adhesive include for examplepolyacrylates, poly acrylic esters, silicones, polyisobutylenes and thelike.

PSAs are generally known in the art. See, e.g., Tan et al., Pharm Sci &Tech Today, 2:60-69 (1999). Non-limiting useful PSAs includepolyisobutylenes (PIB), silicone polymers, acrylate copolymers, andcombinations thereof. In some embodiments, the pressure sensitiveadhesive comprises a polyisobutylene adhesive, a silicone polymeradhesive, an acrylate copolymer adhesive, or a combination thereof. Insome embodiments, the pressure sensitive adhesive comprises an acrylatecopolymer adhesive. Non-limiting useful acrylate copolymers include, forexample, acrylic pressure sensitive adhesives such as a poly acrylatevinyl acetate copolymer, e.g., Duro-Tak 87-2287, Duro-Tak 87-4098,Duro-Tak 87-4287, or Duro-Tak 87-2516, Duro-Tak 87-2852 or Duro-Tak87-2194), which are manufactured by Henkel Adhesives. PIBs areelastomeric polymers that are commonly used in PSAs, both asprimary-base polymers and as tackifiers. PIBs are homopolymers ofisobutylene and feature a regular structure of a carbon-hydrogenbackbone with only terminal unsaturation. Non-limiting useful PIBsinclude those marketed under the trade name Oppanol by BASF. Thesilicone polymers are a high molecular weight polydimethylsiloxane thatcontains residual silanol functionality (SiOH) on the ends of thepolymer chains. Non-limiting useful silicone PSAs for use inpharmaceutical applications include those available from Dow CorningCorporation, for example under the trade name of BIO-PSA, e.g.,BIO-7-4202. In some embodiments, the adhesive layer is about 0.1 mils toabout 10 mils, e.g., about 1.5 mils to about 10 mils (e.g., about 1.5mils to about 2 mils) thick.

In some embodiments, suitable adhesives include for example thefollowing silicone adhesives from Dow Corning: BIO-PSA 7-410X, BIO-PSA7-420X, BIO-PSA 7-430X, BIO-PSA 7-440X, BIO-PSA 7-450X, BIO-PSA 7-460X,and BIO-PSA Hot Melt Adhesive. In some embodiments, suitable adhesivesinclude for example the following polyacrylate/poly acrylic esteradhesives from Henkel Adhesives: Duro-Tak 87-900A, 87-9301, 87-4098,87-2510, 87-2287, 87-4287, 87-2516, 87-2074, 87-235A, 87-2353, 87-2852,87-2051, 87-2052, 87-2054, 87-2194, 87-2196, 87-6908, 387-2510,387-2287, 387-2516, 387-2353, 387-2051, 387-2051 and 387-2054, GELVA GMS3083, 3253, 788 and 9073. These can for example have hydroxy functionalgroups, carboxylic groups, hydroxy and carboxylic groups, or nofunctional groups (as active as the foregoing). These can for exampleinclude vinyl acetate monomer, or not.

Typically, the transdermal delivery device (e.g., a DIA patch) issupported by a backing layer such as an impermeable backing film, andthe adhesive surface is protected by a release liner prior to use.Various materials can be used as a backing layer for the transdermaldelivery device herein. Typically, the backing layer is impermeable. Forexample, the backing layer can be comprised of impermeable polymericfilms such as polyester (PET) or polyethylene (PE) films. In someembodiments, the backing layer can comprise a polyester, such asScotchpak 9736 or Scotchpak 1012, a polyurethane film, such as Scotchpak9701, or a polyethylene film, such as CoTran 9720. In some embodiments,the backing is part of an overlay, and can be a non-woven fabric, apolyurethane film, or other pliable material to provide flexibility andbetter wear.

The release liner can be manufactured in the desired size for thepresent invention. The release liner can be comprised of silicone orfluoro-polymer coated polyester film. The release liner protects thetransdermal delivery device during storage and is removed before itsuse. Silicone-coated release liners include those manufactured by MylanCorporation, Loparex Corporation, and 3M's Drug Delivery Systems. Thefluoro-polymer coated release liners include those manufactured andsupplied by 3M's Drug Delivery Systems and Loparex. In some embodiments,the release liner comprises 3M's ScotchPak 9744 or Scotchpak 1022.

The transdermal delivery devices herein can also optionally includeother suitable excipients such as humectants, plasticizers,antioxidants, anti-irritants, gel-forming agents, crystallizationinhibitors, drug release modifiers etc. These excipients are within theknowledge of those skilled in the art, and can be found, for example, inthe Handbook of Pharmaceutical Excipients, (7^(th) ed. 2012), the entirecontent of which is hereby incorporated by reference. In someembodiments, additional active ingredient(s) can also be included in thetransdermal delivery device herein.

The transdermal delivery devices (e.g., DIA patches) herein can havedifferent sizes (patch sizes) depending on its application. Typically,the patch sizes can be about 5 cm² to about 300 cm² (e.g., about 5 cm²,about 10 cm², about 20 cm², about 30 cm², about 40 cm², about 50 cm²,about 60 cm², about 80 cm², about 100 cm², about 120 cm², about 150 cm²about 200 cm² or any ranges between the specified values), for example,about 10 cm² to about 100 cm².

When applying the transdermal delivery devices (e.g., DIA patches)herein to a skin of a subject, all of the adhesive surface can become incontact with the skin in theory. Thus, the area of the adhesive surfacedefines a skin contact area, which is also referred herein to as anactive surface area. In some embodiments, the adhesive surface is theonly surface of the transdermal delivery device that is in contact withthe skin upon application, and the active surface area is the same asthe area of the adhesive surface. In some embodiments, the adhesivesurface and one or more other surfaces of the transdermal deliverydevice are in contact with the skin upon application, and the entireskin contact area is the active surface area. In a typical DIA patch,the patch size is the same as the active surface area. Unless otherwiseobvious from context, the unit “/cm²” should be understood as per squarecentimeter of active surface area as defined herein.

The active surface area can determine the doses of the drug to bedelivered. Typically, the active surface area can be about 5 cm² toabout 300 cm² (e.g., about 5 cm², about 10 cm², about 20 cm², about 30cm², about 40 cm², about 50 cm², about 60 cm², about 80 cm², about 100cm², about 120 cm², about 150 cm², about 200 cm² or any ranges betweenthe specified values), for example, about 10 cm² to about 100 cm².

In some embodiments, the transdermal delivery device herein can beconfigured to provide dextromethorphan to a user at least about 2 mg/day(e.g., about 2 mg/day to about 50 mg/day) for a period of time of 1 dayor more, for example, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.For example, in some embodiments, the transdermal delivery device isconfigured to transdermally deliver dextromethorphan to a user about 5mg/day to about 50 mg/day (e.g., about 5 mg/day, about 10 mg/day, about20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, or anyranges between the recited values) for 1 day or more (e.g., 1.5 days, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, or any ranges between therecited values).

The total dextromethorphan loading for the transdermal delivery devicecan be adjusted based on the desired total dose. Typically, the totaldextromethorphan loading exceeds 0.5 mg/cm² (e.g., at least 2 mg/cm², atleast 3 mg/cm², at least 4 mg/cm², at least 5 mg/cm², at least 6 mg/cm²,etc.). For example, in some embodiments, the transdermal delivery devicecan have a total dextromethorphan loading of about 0.5 mg/cm² to about 8mg/cm², e.g., about 2 mg/cm² to about 6 mg/cm² (e.g., about 2 mg/cm²,about 3 mg/cm², about 4 mg/cm², about 5 mg/cm², about 6 mg/cm², or anyranges between the recited values). As used herein, the totaldextromethorphan loading of a patch can be calculated by dividing thetotal amount of the dextromethorphan in the patch by the patch's activesurface area.

TDD with a Reservoir Layer

In some embodiments, a reservoir layer can be optionally included in thetransdermal delivery device herein. For example, for high daily dosesand/or application for an extended period of time (e.g., 1 day or more),the reservoir layer can provide more sustained flux of dextromethorphanto a user.

In some embodiments, the transdermal delivery device comprises anadhesive layer comprising an adhesive and a reservoir layer comprisingdextromethorphan. In some embodiments, the adhesive layer optionallycomprises dextromethorphan dispersed in the adhesive. In someembodiments, the adhesive layer does not include dextromethorphan, otherthan through equilibrium with the reservoir layer. In some embodiments,the adhesive layer comprises dextromethorphan dispersed in the adhesive.In some embodiments, the reservoir layer comprises dextromethorphan inan adhesive. In some embodiments, the reservoir layer and the adhesivelayer are the same layer. In some embodiments, the reservoir layer issandwiched between the adhesive layer and a backing layer. In someembodiments, the reservoir layer can be sandwiched between two adhesivelayers which can be the same or different. For example, in someembodiments, the two adhesive layers can have the same ingredients withthe same concentrations, and in some embodiments, can also have the samethickness. However, in some embodiments, the two adhesive layers canhave different ingredients, or same ingredients with differentconcentrations, or have different thickness, etc. An exemplaryconfiguration can be seen in FIG. 3, where the adhesive layer is the toplayer, and the backing layer or an adhesive layer, which can be the sameas or different from the top layer, is the bottom layer, and thereservoir layer is the middle layer.

In some embodiments, the reservoir layer is separated from the adhesivelayer by a membrane, e.g., a rate controlling membrane such as amicroporous membrane. The reservoir layer preferably contains anadhesive; however, other designs of the reservoir layer are alsosuitable when compatible with the adhesive layer and the backing layer.For example, in some embodiments, the reservoir layer can be ascrim/nonwoven fabric saturated with dextromethorphan, or havingdextromethorphan dispersed in other suitable carrier/substrate.

Dextromethorphan can be included in the adhesive layer and reservoirlayer in various concentrations. Typically, the concentration ofdextromethorphan in the reservoir layer is higher than that in theadhesive layer. For example, in some embodiments, the adhesive layer cancomprise dextromethorphan in an amount of about 2% to about 12% (e.g.,about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, or anyrange between the recited values) by weight of the adhesive layer;whereas the reservoir layer can comprise dextromethorphan in an amountof about 20% or more, for example, about 30% or more, about 40% or more,about 50% or more, such as about 20% to about 60%, about 30% to about50%, by weight of the reservoir layer. In some embodiments, the adhesivelayer comprises dextromethorphan in an amount of about 6% to about 12%(e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%,about 12%, or any ranges between the recited values) by weight of theadhesive layer. In some embodiments, the adhesive layer comprisesdextromethorphan at or near the saturation concentration in theadhesive, for example, about 10% by weight in an acrylate adhesive. Insome embodiments, the reservoir layer comprises dextromethorphan abovethe saturation concentration in the adhesive. In other words, thedextromethorphan in the reservoir layer is oversaturated and cantherefore contain solid dextromethorphan, which can serve as a drugdepot.

Suitable adhesives for the adhesive layer and the reservoir layer, asapplicable, include any of those described herein, preferably pressuresensitive adhesives. The adhesives included in the adhesive layer andreservoir layer can be the same or different. In some embodiments, theadhesives included in the adhesive layer and reservoir layer are thesame, for example, acrylate based adhesives. Other suitable adhesivesinclude a polyisobutylene adhesive, a silicone polymer adhesive, anacrylate copolymer adhesive (e.g., a poly acrylate vinyl acetatecopolymer, such as Duro-Tak 87-2287), or a combination thereof. In anyof the embodiments described herein, the adhesive layer can beconfigured for adhering to a user's skin continuous for at least 1 day(e.g., at least 2 days, at least 3 days, at least 4 days, at least 5days, at least 6 days, at least 7 days).

The adhesive (e.g., a pressure sensitive adhesive) typically is the mainingredient for the adhesive layer and reservoir layer (as applicable).For example, in some embodiments, the adhesive layer comprises apressure sensitive adhesive in an amount of about 50% to about 90% byweight of the adhesive layer. In some embodiments, the pressuresensitive adhesive is present in an amount of about 60% to about 85%(e.g., about 60%, about 70%, about 75%, about 80%, about 85%, or anyranges between the recited values) by weight of the adhesive layer. Insome embodiments, the reservoir layer can include a pressure sensitiveadhesive in an amount of about 20% to about 80% by weight of thereservoir layer. For example, in some embodiments, the pressuresensitive adhesive is present in an amount of about 20% to about 65%(e.g., about 20%, about 30%, about 35%, about 40%, about 50%, about 60%,about 65%, or any ranges between the recited values) by weight of thereservoir layer.

Suitable sizes for the transdermal delivery device are described herein.In some embodiments, the transdermal delivery device has an activesurface area of about 5 cm² to about 200 cm². In some embodiments, thetransdermal delivery device has an active surface area of about 10 cm²to about 150 cm². In some embodiments, the transdermal delivery devicehas an active surface area of about 30 cm² to about 100 cm² (e.g., about30 cm², about 40 cm², about 50 cm², about 60 cm², about 70 cm², about 80cm², about 90 cm², about 100 cm², or any ranges between the recitedvalues).

The adhesive layer and reservoir layer can be of various thickness. Forexample, in some embodiments, the adhesive layer is about 0.1 mil toabout 10 mils thick (e.g., about 0.5 mil to about 10 mils, about 1 milto 10 mils). In some embodiments, the reservoir layer can also be about0.1 mil to about 10 mils thick (e.g., about 0.5 mil to about 10 mils,about 1 mil to 10 mils).

Skin permeation enhancers can also be included in the adhesive layer andthe reservoir layer. For example, in some embodiments, the adhesivelayer comprises a skin permeation enhancer selected from isopropylmyristate, oleyl oleate, oleic acid, glycerol monooleate, other fattyacids and fatty acid esters with carbon chain lengths of C₁₂ to C₁₈, andcombinations thereof. In some embodiments, the adhesive layer comprisesisopropyl myristate. Similarly, in some embodiments, the reservoir layercomprises a skin permeation enhancer selected from isopropyl myristate,oleyl oleate, oleic acid, glycerol monooleate, other fatty acids andfatty acid esters with carbon chain lengths of C₁₂ to C₁₈, andcombinations thereof. In some embodiments, the reservoir layer comprisesisopropyl myristate.

Various amounts of skin permeation enhancers can be used for theadhesive layer and the reservoir layer. Typically, the skin permeationenhancer can be present in an amount of about 2% to about 15% by weightof the adhesive layer or reservoir layer. For example, in someembodiments, the skin permeation enhancer is present in an amount ofabout 6% to about 12% (e.g., about 6%, about 7%, about 8%, about 9%,about 10%, about 11%, about 12%, or any ranges between the recitedvalues) by weight of the adhesive layer. In some embodiments, the skinpermeation enhancer is present in an amount of about 6% to about 12%(e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 11%,about 12%, or any ranges between the recited values) by weight of thereservoir layer. However, in some embodiments, the adhesive layer and/orthe reservoir layer can also be substantially free of a skin permeationenhancer selected from isopropyl myristate, oleyl oleate, oleic acid,glycerol monooleate, other fatty acids and fatty acid esters with carbonchain lengths of C₁₂ to C₁₈, and combinations thereof.

In some embodiments, the adhesive layer and/or the reservoir layer caninclude an agent selected from a vinylpyrrolidone polymer (e.g., avinylpyrrolidone-vinyl acetate copolymers), Kollidon (e.g., Kollidon 30LP, Kollidon 90, or Kollidon VA64), silicone dioxide, titanium dioxide,and combinations thereof. In some embodiments, the agent can be presentin an amount of about 2% to about 20% (e.g., about 2%, about 2.5%, about3%, about 4%, about 5%, about 6%, about 10%, about 15%, about 20%, orany ranges between the recited values) by weight of the adhesive layeror reservoir layer. Without wishing to be bound by theories, it isbelieved that such agents can improve the cohesive strength of theadhesive layer or reservoir layer. Further, such agents can have otherfunctions such as inhibiting crystallization. In some embodiments, theadhesive layer comprises an agent effective for improving cohesivestrength of the adhesive layer. In some embodiments, the reservoir layercomprises an agent effective for improving cohesive strength of thereservoir layer.

It should be noted that the identities of ingredients such as adhesives,skin permeation enhancers, agents, and amounts thereof, for the adhesivelayer and the reservoir layer are independently selected, which can bethe same or different. Typically, the amounts can vary whereas theidentity can be the same. The thickness of the adhesive layer and thereservoir layer can also be the same or different.

TDD with a Mixture of Adhesives

As detailed in the Examples section, varying the adhesive components canaffect the flux characteristics of the transdermal delivery devicecomprising dextromethorphan. Thus, in some embodiments, the presentdisclosure also provides a transdermal delivery device comprising anadhesive layer, wherein the adhesive layer comprises two or moreadhesives. Typically, the adhesive layer comprises dextromethorphandispersed in the two or more adhesives.

In some embodiments, the adhesive layer can include a mixture of anacrylate copolymer adhesive (e.g., Durotak 87-2287) and a siliconeadhesive (e.g., BIO-7-4202) in various ratios (e.g., a weight ratio ofacrylate adhesive to silicone adhesive ranging from about 1:20 to about20:1). In some embodiments, the weight ratio of the acrylate adhesive tosilicon adhesive ranges from about 10:1 to about 1:10 (e.g., about 10:1,about 4:1, about 1:1, about 1:4, or any ranges between the recitedvalue). Other ingredients and suitable amounts that can be optionallyincluded in the adhesive layer, such as skin permeation enhancers,include those described herein.

The adhesive layer with two or more adhesives can be included/used inany of the transdermal delivery device herein. For example, in someembodiments, the transdermal delivery device comprising a reservoirlayer described herein can have an adhesive layer with a mixture of anacrylate copolymer adhesive (e.g., Durotak 87-2287) and a siliconeadhesive (e.g., BIO-7-4202) in various ratios.

TDD with a Skin Permeation Enhancer

Skin permeation enhancers (transdermal enhancers) can enhance the skinpermeability of dextromethorphan through the skin and can be optionallyincluded in the transdermal delivery device herein. Various skinpermeation enhancers can be included. Non-limiting useful skinpermeation enhancers include, for example, sulfoxides (e.g.,dimethylsulfoxide, DMSO), Azones (e.g., laurocapram), pyrrolidones(e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol ordecanol), esters, glycols (e.g., propylene glycol (PG)), surfactants(e.g., Tween 80), terpenes, and combinations thereof. See, e.g.,Williams et al., Adv Drug Deliv Rev. 27;56(5):603-18 (2004). In someembodiments, the permeation enhancer comprises one or more compoundschosen from sulfoxides, alcohols, alkanols, esters, glycols, andsurfactants. In some embodiments, the permeation enhancer comprises oneor more compounds chosen from dimethyl sulfoxide (DMSO), oleic alcohol,oleayl oleate, oleic acid, levulinic acid, other fatty acids andfatty-acid esters, propylene glycol, dipropylene glycol, ethanol, andsurfactants such as Tween 80. In some embodiments, the transdermaldevice can include one or more compounds chosen from DMSO,N-methyl-2-pyrolidone, azone, myristic acid, sesquiterpene oil,4-decyloxazolidin-2-one, urea, and the like. In some embodiments, theskin permeation enhancer is selected from isopropyl myristate, oleyloleate, oleic acid, glycerol monooleate, other fatty acids and fattyacid esters with carbon chain lengths of C₁₂ to C₁₈, and combinationsthereof. In some specific embodiments, the skin permeation enhancer isisopropyl myristate.

The skin permeation enhancer is typically included in the amount ofabout 1% to about 25% by weight of an adhesive layer, for example, about2%, about 5%, about 10%, about 15%, about 20%, about 25%, or any rangesbetween the specified values, by weight of the adhesive layer. In someembodiments, the transdermal device can be substantially free of atransdermal enhancer. In some embodiments, the transdermal device issubstantially free of a transdermal enhancer if the amount of anypotential such enhancers is about 20% or less than the least amount thathas been shown to enhance transdermal flux by about 50% or more.

In some embodiments, the skin permeation enhancer and its amount arechosen to provide certain improved flux characteristics. For example, insome embodiments, the present disclosure provides a transdermal deliverydevice comprising an adhesive layer comprising dextromethorphandispersed in an adhesive, wherein the adhesive layer comprises a skinpermeation enhancer in an amount to provide a mean cumulativedextromethorphan permeated at 24 hours post application of at leastabout 25% (e.g., about 25%, about 50%, about 100%, about 150%, about200%, or any ranges between the recited value) higher than that of anotherwise equivalent transdermal delivery device without the skinpermeation enhancer, when tested in vitro using human cadaver skin. Theterm “otherwise equivalent transdermal delivery device without the skinpermeation enhancer” should be understood as a control transdermaldelivery device, wherein the content of the skin permeation enhancer inthe adhesive layer is replaced with the adhesive, with all other aspectsthe same. For example, a transdermal delivery device includes anadhesive layer comprising 10% by weight of a skin permeation enhancerand 10% by weight dextromethorphan dispersed in 80% by weight acrylateadhesive, the otherwise equivalent device would include a respectiveadhesive layer with 10% by weight dextromethorphan dispersed in 90% byweight of the same acrylate adhesive, with all other aspects of the twodevices being the same.

The skin permeation enhancer and its amount can also be adjusted toachieve flux enhancement at different time points post application. Forexample, in some embodiments, the permeation enhancer is in an amount toprovide one or more of the following: 1) a mean average flux ofdextromethorphan from 8 hours to 24 hours post application of at leastabout 25% (e.g., about 25%, about 50%, about 100%, about 150%, about200%, or any ranges between the recited value) higher than that of anotherwise equivalent transdermal delivery device without the skinpermeation enhancer; 2) a mean average flux of dextromethorphan from 4hours to 8 hours post application of at least about 2-fold (e.g., about3-fold, about 4-fold, about 5-fold, about 8-fold, about 10-fold, or anyranges between the recited value) of that of an otherwise equivalenttransdermal delivery device without the skin permeation enhancer; and 3)a mean average flux of dextromethorphan from 0 hours to 4 hours postapplication of at least about 5-fold (e.g., about 5-fold, about 8-fold,about 10-fold, about 20-fold, or any ranges between the recited value)of that of an otherwise equivalent transdermal delivery device withoutthe skin permeation enhancer, when tested in vitro using human cadaverskin. As detailed in the Examples, in one example, when the amount ofpermeation enhancer, isopropyl myristate, is increased to about 10% byweight, significant enhancement of flux was observed even at or before 4hours post application.

The adhesive layer with a skin permeation enhancer can be included/usedin any of the transdermal delivery devices herein. For example, in someembodiments, the transdermal delivery device comprising a reservoirlayer described herein can have an adhesive layer with the adhesivelayer with a skin permeation enhancer. Other ingredients and suitableamounts that can be optionally included in the adhesive layer includethose described herein.

In some specific embodiments, the transdermal delivery device caninclude an adhesive layer and a reservoir layer, wherein the adhesivelayer and reservoir layer can, for example, have the ingredients andamounts shown in the table below.

Example Typical amount Preferred Amount Adhesive Layer IngredientsAdhesive Duro-Tak about 65% to about 85% about 75% to about 77.5%287-2287 Drug Dextromethorphan about 2% to about 12% about 10% basePermeation isopropyl about 6% to about 12% about 10% enhancer myristateOthers Kollidon, e.g., about 1% to about 20% about 2.5% to about 5%Kollidon VA64 Reservoir Layer Ingredients Adhesive Duro-Tak about 20% toabout 70% about 20% to about 57.5% 287-2287 Drug Dextromethorphan about20% to about 60% about 30% to about 50% base Permeation isopropyl about6% to about 12% about 10% enhancer myristate Others Kollidon, e.g.,about 1% to about 20% about 2.5% to about 20% Kollidon VA64All amounts in the table refer to the weight percentage of therespective layer (based on final formulation) with the total amount ofeach layer being 100%. In some embodiments, the transdermal deliverydevice can have an active surface area of about 60 cm² or more, e.g.,about 70 cm². In some embodiments, the transdermal delivery device isconfigured to provide dextromethorphan about 15 mg/day to about 40mg/day to a user, for example, about 15 mg/day, about 20 mg/day, about25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, or anyranges between the recited values. In some embodiments, the transdermaldelivery device comprises about 50 mg to about 700 mg (e.g., about 50mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400mg, about 500 mg, about 600 mg, about 700 mg, or any range between therecited values) dextromethorphan. In some embodiments, the reservoirlayer can be sandwiched between two adhesive layers which can be thesame or different. Typically, such transdermal delivery device alsoincludes a backing layer and a release liner which protects the adhesivesurface prior to use. Typically, these patches can be used for a dosingfrequency of less than once a day, for example, once in one day, or twodays or more, e.g., once a week, or 2, 3, 4, 5, or 6 times a week, suchas twice a week.

In some specific embodiments, the transdermal delivery device caninclude an adhesive layer, which can, for example, have the ingredientsand amounts shown in the table below.

Adhesive Layer Ingredients Example Typical amount Preferred AmountAdhesive Duro-Tak about 65% to about 85% about 80%, or about 287-228775% to about 77.5% Drug Dextromethorphan about 2% to about 12% about 10%base Permeation isopropyl about 6% to about 12% about 10% enhancermyristate Others Kollidon, e.g., 0% to about 20% 0%, or about 2.5% toKollidon VA64 about 5%All amounts in the table refer to the weight percentage of the finaladhesive layer with the total amount being 100%. In some embodiments,the transdermal delivery device can have an active surface area of about10 cm² or more, e.g., about 30 cm², about 45 cm², about 60 cm², about 75cm², about 90 cm². In some embodiments, the transdermal delivery deviceis configured to provide dextromethorphan about 15 mg/day to about 40mg/day to a user, for example, about 15 mg/day, about 20 mg/day, about25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, or anyranges between the recited values. In some embodiments, the transdermaldelivery device comprises about 5 mg to about 100 mg (e.g., about 15 mg,about 30 mg, about 45 mg, about 60 mg, about 90 mg, or any range betweenthe recited values) of dextromethorphan. Typically, such transdermaldelivery device also includes a backing layer and a release liner whichprotects the adhesive surface prior to use. Typically, these patches canbe used for a dosing frequency of no less than once a day, for example,once daily, or once in 12 hours, etc.

In Vitro Flux Characteristics

In some embodiments, the transdermal delivery device herein isconfigured to provide certain in vitro dextromethorphan flux profile,e.g., when tested using human cadavar skin. For example, in someembodiments, any of the transdermal delivery devices herein can beconfigured to provide 1) a mean cumulative dextromethorphan permeated ofat least about 200 ug/cm² (ug refers to micrograms) (e.g., about 200ug/cm² to about 2000 ug/cm²) at 24 hours post application; and/or 2) amean average flux of dextromethorphan of at least about 5 ug/cm²*h(e.g., about 5 ug/cm²*h to about 20 ug/cm²*h, about 10 ug/cm²*h to about18 ug/cm²*h) from 8 hours to 24 hours post application, when tested invitro using human cadaver skin.

In some embodiments, the transdermal delivery device can transdermallydeliver to a subject in need thereof at least about 200 ug/cm² (e.g.,about 200 ug/cm² to about 2000 ug/cm²) per day. In some embodiments, thetransdermal delivery device is configured to have a flux characteristicsuch that applying the transdermal delivery device to a subject in needthereof transdermally delivers dextromethorphan about 2 mg/day to about50 mg/day to the subject. In some embodiments, the transdermal deliverydevice can transdermally deliver to the subject about 5 mg/day to about50 mg/day (e.g., about 5 mg/day, about 10 mg/day, about 20 mg/day, about30 mg/day, about 40 mg/day, about 50 mg/day, or any ranges between therecited values) to the subject for 1 day or more (e.g., 1.5 days, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, or any ranges between therecited values). The size of the transdermal delivery device istypically about 5 cm² to about 200 cm², for example, about 10 cm² toabout 100 cm².

Transdermal delivery devices with the above flux characteristics can beprepared by those skilled in the art in view of the present disclosure.Preparations of a few transdermal delivery devices are also exemplifiedin the Examples section. The cumulative drug (dextromethorphan,deuterated dextromethorphan, or a combination thereof) permeated can beadjusted, for example, by varying the composition of the adhesive layer(e.g., drug concentration, permeation enhancer, drug load, types ofadhesives etc.).

It should be noted that the pharmaceutical composition formulated forthe adhesive layer and/or the reservoir layer described herein is also anovel aspect of the present disclosure.

The transdermal delivery device herein can also be characterized bycertain in vivo release profile, e.g., to provide a desiredpharmacokinetic (PK) profile, e.g., any of those described herein. Insome embodiments, the transdermal delivery device can be configured toprovide a PK profile in a subject in need thereof, e.g., any of the PKprofile described herein. In some embodiments, the transdermal deliverydevice is configured to provide a PK profile effective, for example, fortreating a disease or disorder (e.g., described herein, such as PBA) inthe subject.

TDD with Two Different Zones

In some embodiments, the transdermal delivery device can include twodifferent zones with different release rates.

Illustrated in FIG. 7 is a view of a matrix transdermal device 100. Thecenter matrix 20 can be for example configured (drug amount and adhesiveor adhesive mixture selected) to provide more rapid onset. In theillustrative example, the added amount of pharmaceutical active in thecenter matrix 20 can reduce adhesion. Nonetheless, adhesion from thesurrounding matrix 30 holds the device in place. Surrounding matrix 30can be configured for example to provide longer term delivery ofpharmaceutical active.

In embodiments with two different zones, the rapidly releasing portionof the device, can be for example about 5 cm² to about 150 cm², e.g.,about 5 cm² to about 100 cm², or about 5 cm² to about 40 cm², etc. inarea. A slower release portion can be for example about 5 cm² to about150 cm², e.g., about 5 cm² to about 100 cm², or about 7.5 cm² to about55 cm² in area.

Methods of Administering Dextromethorphan and PK Profiles

In various embodiments, the present invention provides a method of usingthe transdermal delivery device or pharmaceutical compositions describedherein, for example, for administering dextromethorphan to a subject inneed thereof, e.g., those suffering from any of the diseases ordisorders described herein.

Some embodiments are directed to a method of administeringdextromethorphan to a subject (e.g., human subject) in need thereof. Insome embodiments, the subject is sensitive to or otherwise intolerant toquinidine, e.g., with QTc prolongation. In some embodiments, the methodcomprises applying any of the transdermal delivery devices orpharmaceutical compositions to the subject, for example, to the skin ofthe subject. In some embodiments, the subject is not administereddextromethorphan through another source, for example, through oraladministration. However, in some embodiments, the subject can also besupplemented with another source of dextromethorphan, for example, byco-administering an oral formulation of dextromethorphan to the subject.In some embodiments, the user is characterized as an extensivemetabolizer. In some embodiments, the user is characterized as a poormetabolizer. In some embodiments, the user is not co-administered aCYP2D6 inhibitor. In some embodiments, the user is not co-administeredquinidine. In some embodiments, the user is co-administered a CYP2D6inhibitor such as quinidine, bupropion, etc.

Various dosing regimen are suitable for the methods herein. For example,in some embodiments, the method comprises administering a transdermaldelivery device (e.g., described herein) to the subject once daily for adesired period of time. In some embodiments, the transdermal deliverydevice comprises about 5 mg to about 100 mg of dextromethorphan. In someembodiments, the method can also comprise administering a transdermaldelivery device (e.g., described herein) to the subject once in two daysor more (e.g., once in two days, once in three days, once in four days,once in five days, once in six days, once in a week, etc.) for a desiredperiod of time. In some embodiments, the method can also compriseadministering a transdermal delivery device (e.g., described herein) tothe subject once in at least one day, for example, once in two days ormore (e.g., once a week), or 1, 2, 3, 4, 5, or 6 times a week for adesired period of time. In some embodiments, the method can alsocomprise administering a transdermal delivery device (e.g., describedherein) to the subject once a week. In some embodiments, the transdermaldelivery device comprises about 50 mg to about 700 mg ofdextromethorphan. While the methods herein typically apply thetransdermal delivery device to the subject in a frequency of once a dayor once in more than 1 day, in some embodiments, the methods can alsoapply the transdermal delivery device to the subject in a frequency ofonce in less than 1 day, such as twice a day or three times a day.

The methods of administering dextromethorphan herein typically providecertain pharmacokinetic profile in a subject (e.g., human subject) inneed thereof that is suitable (e.g., effective), for example, fortreating a disease or disorder (e.g., any of those described herein suchas PBA) in the subject.

In some embodiments, the methods comprise administering the transdermaldelivery device herein to the subject to achieve an average bloodC_(max) of dextromethorphan of about 6 ng/mL to about 21 ng/mL (e.g.,about 8 ng/mL to about 17 ng/mL or about 10 ng/mL to about 15 ng/mL) andthat for a period of twelve hours or more, the A.U.C. ofdextromethorphan is about the equivalent (normalized to the measuringperiod) of the 12 hour value of about 52 ng⋅h/mL to about 144 ng⋅h/mL(e.g., about 65 ng⋅h/mL to about 125 ng⋅h/mL, or about 75 ng⋅h/mL toabout 110 ng⋅h/mL).

As detailed in the Examples section, applying to healthy human anexemplary patch containing about 35 mg dextromethorphan with a size of45 cm², which was designed to transdermally deliver 15 mg per day andcontains, in the adhesive layer (drug-in-adhesive layer) about 80% byweight of an adhesive (Duro-Tak 87-2287), about 10% by weight ofdextromethorphan base and about 10% by weight of permeation enhancerisopropyl myristate, for about 24 hours, achieved, inter alia, a meanC_(max) of about 6 ng/mL and a mean AUC_(0-24h) of about 92 h-ng/mL,which are approaching those observed from orally administering acombination of 20 mg dextromethorphan and 10 mg quinidine twice a day tothe human subject. This shows for the first time that transdermaldelivery of dextromethorphan, without using quinidine, can provide asignificant blood level of dextromethorphan in human. Further, the humanPK data allows a skilled person to adjust the patch design to achieve adesired PK profile.

For example, in some embodiments, the method comprises, consistsessentially of, or consists of, applying a transdermal delivery device(e.g., described herein) comprising dextromethorphan to the skin of thesubject (e.g., human subject) once daily (e.g., for up to 7 days or moreor for at least 7 days or any desired period of time), wherein theapplying results in one or more (1, 2, 3, 4, 5, 6, 7, 8, or all), in anycombinations, of the following pharmacokinetic profile in thesubject: 1) a mean C_(max) of dextromethorphan of at least about 3 ng/ml(e.g., about 3 ng/ml to about 12 ng/ml) at day 1 post application (i.e.,measured for the period from time 0 to 24 hours post application); 2) amean AUC₀₋₂₄ of dextromethorphan of at least about 40 ng*h/ml (e.g.,about 40 ng*h/ml to about 150 ng*h/ml) at day 1 post application; 3) amean ratio of C_(24h)/C_(12h) of dextromethorphan of not more than about1.5 (e.g., about 1 to about 1.5) at day 1 post application; 4) a meanratio of C_(24h)/C_(6h) of dextromethorphan of at least about 1.2 (e.g.,about 1.5 to about 2.5) at day 1 post application; 5) a mean ratio ofC_(24h)/C_(18h) of dextromethorphan of about 0.85 to about 1.3 at day 1post application; 6) a mean C_(max) of dextrorphan of not more than 2ng/ml (e.g., not more than 2 ng/ml, not more than 1 ng/ml, or not morethan 0.5 ng/ml) at day 1 post application; 7) a mean AUC₀₋₂₄ ofdextrorphan of not more than 10 ng*h/ml (e.g., not more than 10 ng*h/mlor not more than 5 ng*h/ml) at day 1 post application; 8) a mean ratioof C_(max) of dextromethorphan to C_(m) of dextrophan of at least about5 (e.g., at least about 10, at least about 15, at least about 20) at day1 post application; and 9) a mean ratio of AUC₀₋₂₄ of dextromethorphanto AUC₀₋₂₄ of dextrophan of at least about 5 (e.g., at least about 10,at least about 15, at least about 20, or at least about 25) at day 1post application. In some embodiments, the applying results in a PKprofile in the subject comprising: a). 1) and/or 2); b). 3), 4), and/or5); c). 6) and/or 7); d). 8) and/or 9); or e). any combination of a),b), c), and d).

In some embodiments, the method can comprise, consist essentially of, orconsist of, applying a transdermal delivery device (e.g., describedherein) comprising dextromethorphan to the skin of the subject (e.g.,human subject) once in at least one day (e.g., once in two days or more(e.g., once in two days, once in three days, once in four days, once infive days, once in six days, once in a week, etc.) (e.g., for up to 7days or more or for at least 7 days or any desired period of time),wherein the applying results in one or more (1, 2, 3, 4, 5, 6, 7, 8, orall), in any combinations, of the following pharmacokinetic profile inthe subject: 1) a mean C_(max) of dextromethorphan of at least about 3ng/ml (e.g., about 3 ng/ml to about 12 ng/ml) at day 1 post application;2) a mean AUC₀₋₂₄ of dextromethorphan of at least about 40 ng*h/ml(e.g., about 40 ng*h/ml to about 150 ng*h/ml) at day 1 post application;3) a mean ratio of C_(24h)/C_(12h) of dextromethorphan of not more thanabout 1.5 (e.g., about 1 to about 1.5) at day 1 post application; 4) amean ratio of C_(24h)/C_(6h) of dextromethorphan of at least about 1.2(e.g., about 1.5 to about 2.5) at day 1 post application; 5) a meanratio of C_(24h)/C_(18h) of dextromethorphan of about 0.85 to about 1.3at day 1 post application; 6) a mean C_(max) of dextrorphan of not morethan 2 ng/ml (e.g., not more than 2 ng/ml, not more than 1 ng/ml, or notmore than 0.5 ng/ml) at day 1 post application; 7) a mean AUC₀₋₂₄ ofdextrorphan of not more than 10 ng*h/ml (e.g., not more than 10 ng*h/mlor not more than 5 ng*h/ml) at day 1 post application; 8) a mean ratioof C_(max) of dextromethorphan to C_(max) of dextrophan of at leastabout 5 (e.g., at least about 10, at least about 15, at least about 20)at day 1 post application; and 9) a mean ratio of AUC₀₋₂₄ ofdextromethorphan to AUC₀₋₂₄ of dextrophan of at least about 5 (e.g., atleast about 10, at least about 15, at least about 20, or at least about25) at day 1 post application. In some embodiments, the applying resultsin a PK profile in the subject comprising: a). 1) and/or 2); b). 3), 4),and/or 5); c). 6) and/or 7); d). 8) and/or 9); or e). any combination ofa), b), c), and d). In some embodiments, the method with a once at least1 day application results in substantially the same PK profile for day 1post application as that observed with the once daily method describedherein.

The plasma concentration from the transdermal delivery device herein canbe maintained substantially constant and the peak to trough ratio istypically lower than those observed from orally administering Neudextatwice a day. For example, in some embodiments, the method comprisesapplying the transdermal delivery device to the skin of the subject(e.g., human subject) once a week, wherein the applying results in i) amean ratio of C_(24h)/C_(12h) of dextromethorphan of not more than 2(e.g., about 0.85 to about 1.3) at day 7 post application; ii) a meanratio of C_(24h)/C_(6h) of dextromethorphan of not more than 2 (e.g.,about 0.85 to about 1.3) at day 7 post application; and/or iii) a meanratio of C_(24h)/C_(18h) of dextromethorphan of not more than 2 (e.g.,about 0.85 to about 1.3) at day 7 post application. In some embodiments,the applying results in at least two of i)-iii). In some embodiments,the applying results in all of i)-iii). The once daily methods describedherein can also result in a relatively low peak to trough ratio, whichis typically lower than the corresponding ratio observed from orallyadministering Neudexta twice a day, for example, when measured for atime period after steady state is reached.

In some embodiments, the methods herein can be adjusted to achieve aC_(max) and/or AUC of dextromethorphan according to different needs, forexample, to match (or approach) those observed for orally administeringa combination of 20 mg dextromethorphan and 10 mg quinidine twice a day.

For example, in some embodiments, the method comprises applying thetransdermal delivery device herein to the subject (e.g., human subject)once daily or once a week, for up to 7 days or more or for at least 7days or any desired period of time, wherein the applying results in i) amean C_(max) of dextromethorphan of at least about 8 ng/ml (e.g., about8 ng/ml to about 20 ng/ml) at day 7 post application; and/or ii) a meanC_(max) of dextrorphan of not more than 2 ng/ml (e.g., e.g., not morethan 2 ng/ml, not more than 1 ng/ml, or not more than 0.5 ng/ml) at day7 post application. In some embodiments, the applying results in one ormore of the following PK profile: a) a mean C_(max) of dextromethorphanof at least about 30% (e.g., about 30% to about 80%) of that observedfrom orally administering a combination of 20 mg dextromethorphan and 10mg quinidine twice a day to the subject (e.g., human subject) for 7days; b) a mean AUC₀₋₂₄ of dextromethorphan of at least about 30% (e.g.,about 30% to about 80%) of that observed from orally administering acombination of 20 mg dextromethorphan and 10 mg quinidine twice a day tothe subject (e.g., human subject) for 7 days; c) a mean C_(max) ofdextrorphan of not more than about 50% (e.g., about 10% to about 30%) ofthat observed from orally administering a combination of 20 mgdextromethorphan and 10 mg quinidine twice a day to the subject (e.g.,human subject) for 7 days; and d) a mean AUC₀₋₂₄ of dextrorphan of notmore than about 50% (e.g., about 10% to about 30%) of that observed fromorally administering a combination of 20 mg dextromethorphan and 10 mgquinidine twice a day to the subject (e.g., human subject) for 7 days,when measured at day 7 post application.

The methods herein are not limited to a particular subject or aparticular class of subjects. In some embodiments, the subject ischaracterized as an extensive metabolizer. In some embodiments, thesubject is characterized as a poor metabolizer. In some embodiments, thesubject is not co-administered a CYP2D6 inhibitor. In some embodiments,the subject is not co-administered quinidine. In some embodiments, thesubject is co-administered a CYP2D6 inhibitor such as quinidine,bupropion, etc. However, in any of the embodiments described herein, thesubject does not suffer from a cough and/or does not need anantitussive.

In some embodiments, the subject (e.g., human subject) is characterizedas having a neurological disease or disorder. In some embodiments, thesubject (e.g., human subject) is characterized as having one or morediseases or disorders selected from affective disorders, psychiatricdisorders, cerebral function disorders, movement disorders, dementias,motor neuron diseases, neurodegenerative diseases, seizure disorders,and headaches. In some embodiments, the subject suffers from one or morediseases or disorders selected from depression, major depression,treatment resistant depression, treatment resistant bipolar depression,bipolar disorders including cyclothymia, seasonal affective disorder,mood disorders, chronic depression (dysthymia), psychotic depression,postpartum depression, premenstrual dysphoric disorder (PMDD),situational depression, atypical depression, mania, anxiety disorders,attention deficit disorder (ADD), attention deficit disorder withhyperactivity (ADDH), attention deficit/hyperactivity disorder (AD/HD),bipolar and manic conditions, obsessive-compulsive disorder, bulimia,obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.In some embodiments, the subject suffers from one or more diseases ordisorders selected from Alzheimer's disease, prion-related diseases,cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy(SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington'sdisease, Lewy body disease, Parkinson's disease, amyotrophic lateralsclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS),multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration,progressive supranuclear palsy, Wilson's disease, Menkes disease,adrenoleukodystrophy, cerebral autosomal dominant arteriopathy withsubcortical infarcts and leukoencephalopathy (CADASIL), musculardystrophies, Charcot-Marie-Tooth disease (CMT), familial spasticparaparesis, neurofibromatosis, olivopontine cerebellar atrophy ordegeneration, striatonigral degeneration, Guillain-Barré syndrome, andspastic paraplesia. In any of the embodiments herein, the subject cansuffer from pseudobulbar affect, depression, stroke, traumatic braininjury, seizure, pain (e.g., post-operative pain, neuropathic pain),methotrexate neurotoxicity, Parkinson's disease, autism, or combinationsthereof. In any of the embodiments herein, the subject can suffer frompseudobulbar affect.

Methods of Treatment

Dextromethorphan are known to be useful for treating a variety ofdiseases or disorders. See e.g., Nguyen, L. et al., Pharmacology&Therapeutics 159:1022 (2016). Thus, in some embodiments, the presentdisclosure is also directed to a method of treating a disease ordisorder in a subject in need thereof. In some embodiments, the methodcomprises transdermally administering to the subject a therapeuticallyeffective amount of dextromethorphan. In some embodiments, theadministering comprises applying the transdermal delivery device to theskin of the subject. In some embodiments, the administering results in aPK profile described herein. In some embodiments, the subject does notsuffer from a cough and/or does not need an antitussive agent. In someembodiments, the subject is an extensive metabolizer ofdextromethorphan. In some embodiments, the subject is a poor metabolizerof dextromethorphan. In some embodiments, the subject is sensitive to orotherwise intolerant to quinidine, e.g., with QTc prolongation.

Various diseases and disorders are suitable to be treated by the methodsherein. In some embodiments, the disease or disorder is a neurologicaldisorder. Non-limiting exemplary neurological diseases or disordersinclude affective disorders, psychiatric disorders, cerebral functiondisorders, movement disorders, dementias, motor neuron diseases,neurodegenerative diseases, seizure disorders, and headaches.

Affective disorders that can be treated by methods herein include, butare not limited to, depression, major depression, treatment resistantdepression and treatment resistant bipolar depression, bipolar disordersincluding cyclothymia, seasonal affective disorder, mood disorders,chronic depression (dysthymia), psychotic depression, postpartumdepression, premenstrual dysphoric disorder (PMDD), situationaldepression, atypical depression, mania, anxiety disorders, attentiondeficit disorder (ADD), attention deficit disorder with hyperactivity(ADDH), and attention deficit/hyperactivity disorder (AD/HD), bipolarand manic conditions, obsessive-compulsive disorder, bulimia, obesity orweight-gain, narcolepsy, chronic fatigue syndrome, premenstrualsyndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Psychiatric disorders that can be treated by the methods herein include,but are not limited to, anxiety disorders, including but not limited to,phobias, generalized anxiety disorder, social anxiety disorder, panicdisorder, agoraphobia, obsessive-compulsive disorder, and post-traumaticstress disorder (PTSD); mania, manic depressive illness, hypomania,unipolar depression, depression, stress disorders, somatoform disorders,personality disorders, psychosis, schizophrenia, delusional disorder,schizoaffective disorder, schizotypy, aggression, aggression inAlzheimer's disease, agitation, and agitation in Alzheimer's disease.

Substance addiction abuse that can be treated by the methods hereininclude, but is not limited to, drug dependence, addiction to cocaine,psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol,opioids, anxiolytic and hypnotic drugs, cannabis (marijuana),amphetamines, hallucinogens, phencyclidine, volatile solvents, andvolatile nitrites. Nicotine addiction includes nicotine addiction of allknown forms, such as smoking cigarettes, cigars and/or pipes, andaddiction to chewing tobacco.

Cerebral function disorders that can be treated by the methods hereininclude, but are not limited to, disorders involving intellectualdeficits such as senile dementia, Alzheimer's type dementia, memoryloss, amnesia/amnestic syndrome, epilepsy, disturbances ofconsciousness, coma, lowering of attention, speech disorders, voicespasms, Parkinson's disease, Lennox-Gastaut syndrome, autism,hyperkinetic syndrome, and schizophrenia. Cerebral function disordersalso include disorders caused by cerebrovascular diseases including, butnot limited to, stroke, cerebral infarction, cerebral bleeding, cerebralarteriosclerosis, cerebral venous thrombosis, head injuries, and thelike where symptoms include disturbance of consciousness, seniledementia, coma, lowering of attention, and speech disorders.

Movement disorders that can be treated by the methods herein include,but are not limited to, akathisia, akinesia, associated movements,athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebralpalsy, chorea, Huntington's disease, rheumatic chorea, Sydenham'schorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm,spasmodic torticollis, dopamine-responsive dystonia, Parkinson'sdisease, restless legs syndrome (RLS), tremor, essential tremor, andTourette's syndrome, and Wilson's disease.

Dementias that can be treated by the methods herein include, but are notlimited to, Alzheimer's disease, Parkinson's disease, vascular dementia,dementia with Lewy bodies, mixed dementia, fronto-temporal dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington'sdisease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that can be treated by the methods herein include,but are not limited to, amyotrophic lateral sclerosis (ALS), progressivebulbar palsy, primary lateral sclerosis (PLS), progressive muscularatrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA),spinal motor atrophies, Tay-Sach's disease, Sandoff disease, andhereditary spastic paraplegia.

Neurodegenerative diseases that can be treated by the methods hereininclude, but are not limited to Alzheimer's disease, prion-relateddiseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinalmuscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiplesclerosis (MS), multiple system atrophy, Shy-Drager syndrome,corticobasal degeneration, progressive supranuclear palsy, Wilson'sdisease, Menkes disease, adrenoleukodystrophy, cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT),familial spastic paraparesis, neurofibromatosis, olivopontine cerebellaratrophy or degeneration, striatonigral degeneration, Guillain-Barrésyndrome, and spastic paraplesia.

Seizure disorders that can be treated by the methods herein include, butare not limited to, epileptic seizures, nonepileptic seizures, epilepsy,febrile seizures; partial seizures including, but not limited to, simplepartial seizures, Jacksonian seizures, complex partial seizures, andepilepsia partialis continua; generalized seizures including, but notlimited to, generalized tonic-clonic seizures, absence seizures, atonicseizures, myoclonic seizures, juvenile myoclonic seizures, and infantilespasms; and status epilepticus.

Types of headaches that can be treated by the methods herein include,but are not limited to, migraine, tension, and cluster headaches.

Other neurological disorders that can be treated by the methods hereininclude, but are not limited to, Rett Syndrome, autism, tinnitus,disturbances of consciousness disorders, sexual dysfunction, intractablecoughing, narcolepsy, cataplexy; voice disorders due to uncontrolledlaryngeal muscle spasms, including, but not limited to, abductorspasmodic dysphonia, adductor spasmodic dysphonia, muscular tensiondysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-inducedneurotoxicity, such as methotrexate neurotoxicity; incontinenceincluding, but not limited, stress urinary incontinence, urge urinaryincontinence, and fecal incontinence; and erectile dysfunction.

In some embodiments, the disease or disorder is pain, joint pain, painassociated with sickle cell disease, pseudobulbar affect, depression(including treatment resistant depression), disorders related to memoryand cognition, schizophrenia, Parkinson's disease, amyotrophic lateralsclerosis (ALS), Rhett's syndrome, seizures, cough (including chroniccough), etc.

The methods herein can also be used to treat, or provide relief to, anytype of pain including, but not limited to, musculoskeletal pain,neuropathic pain, cancer-related pain, acute pain, nociceptive pain,inflammatory pain, arthritis pain, complex regional pain syndrome, etc.

In some embodiments, the disease or disorder can be allodynia, treatmentrefractory hyperalgesia, dermatitis, pain, inflammation or inflammatoryconditions, such as Crohn's disease, including pain associated withinflammation, psoriasis, cancer, viral infection, or as an adjuvanttreatment for multiple myeloma.

In any of the embodiments described herein, the method can be fortreating pseudobulbar affection, depression, stroke, traumatic braininjury, seizure, pain (e.g., post-operative pain, neuropathic pain),methotrexate neurotoxicity, Parkinson's disease, autism, or acombination thereof.

Suitable dosing regimen, dosing amount, duration, transdermal deliverydevices, etc. include any of those described herein in any combination.In any of the embodiments described herein, the subject can be a humansubject.

In some specific embodiments, the present disclosure provides a methodof treating pseudobulbar affection comprising applying the transdermaldelivery device herein to a subject in need thereof. In someembodiments, the transdermal delivery device comprises about 5 mg toabout 100 mg of dextromethorphan. In some embodiments, the transdermaldelivery device is applied once daily, e.g., for a period of time up to7 days, at least 7 days, 1 month, or any period of time desired. In someembodiments, the transdermal delivery device comprises about 50 mg toabout 700 mg of dextromethorphan. In some embodiments, the transdermaldelivery device is applied once a week, e.g., for 1 week, 1 month, orany period of time desired. In some embodiments, the transdermaldelivery device is applied 1, 2, 3, 4, 5, or 6 times in a week, e.g.,for 1 week, 1 month, or any period of time desired. In some embodiments,the transdermal delivery device is applied to achieve any of thepharmacokinetic profile described herein. In some embodiments, thesubject is not administered a CYP2D6 inhibitor. In some embodiments, thesubject is not administered quinidine. In some embodiments, the subjectdoes not suffer from a cough or need an antitussive effect. In someembodiments, the subject is characterized as a poor metabolizer. In someembodiments, the subject is characterized as an extensive metabolizer.

Combination Therapy

In some embodiments, the methods herein can further compriseadministering to the subject an active agent other thandextromethorphan. For example, in some embodiments, the method describedherein further comprises administering to the subject an antidepressant.In some embodiments, the antidepressant is selected from bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, ametabolite or prodrug of any of these compounds, and combinationsthereof. Other suitable antidepressants are described for example inU.S. Pat. No. 9,861,595, the content of which is incorporated byreference in its entirety. In some embodiments, the method describedherein further comprises administering to the subject quinidine. In someembodiments, the method described herein further comprises administeringto the subject a CYP2D6 inhibitor. In some embodiments, the methoddescribed herein further comprises administering to the subject one ormore additional active agents selected from amlodipine, a capsaicinoid(e.g., capsaicin or an ester thereof), an opioid agonist (e.g., aμ-opiate analgesic (e.g., tramadol)), an adenosinergic agonist,3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin, andpharmaceutically acceptable salts thereof. These additional agents canbe administered simultaneously or sequentially. Further, theseadditional agents can be administered via the same or a different route.For example, in some embodiments, the additional agent can beadministered transdermally or orally. However, in some embodiments, theadditional agent can also be combined with dextromethorphan in the sametransdermal delivery device.

Because the transdermal application described herein bypasses thefirst-pass liver metabolism, the methods herein can providedextromethorphan to subjects who are on medications that might interferewith liver metabolism of dextromethorphan. In some embodiments, themethod comprises administering to the subject desipramine, paroxetine,thioridazine, pimozide, digoxin, atazanavir, clarithromycin, indinavir,itraconazole, ketoconazole, and combinations thereof. However, in someembodiments, the subject is not administered any of desipramine,paroxetine, thioridazine, pimozide, digoxin, atazanavir, clarithromycin,indinavir, itraconazole, ketoconazole, and combinations thereof. In someembodiments, the method does not require determining and/or is withoutregard to whether the subject is an extensive metabolizer or poormetabolizer of dextromethorphan.

Definitions

As used herein, the term “about” modifying an amount related to theinvention refers to variation in the numerical quantity that can occur,for example, through routine testing and handling; through inadvertenterror in such testing and handling; through differences in themanufacture, source, or purity of ingredients/materials employed in theinvention; and the like. As used herein, “about” a specific value alsoincludes the specific value, for example, about 10% includes 10%.Whether or not modified by the term “about”, the claims includeequivalents of the recited quantities. In one embodiment, the term“about” means within 20% of the reported numerical value.

As used herein, the term “cumulative drug permeated” refers to the totalamount of drug permeated per square centimeter during a given period oftime. Unless otherwise obvious from context, “cumulative drug permeated”at a given time (e.g., at 24 hours post administration) refers to thetotal amount of drug permeated per square centimeter from time 0 (i.e.,time of administration) to the given time. Unless otherwise obvious fromcontext, “cumulative drug permeated” refers to the arithmetic mean valuemeasured and/or calculated in accordance with the methods describedherein. The term “mean value” as used herein, when not specified, alsorefers to arithmetic mean value, unless contradictory to common practicein the field.

As used herein, the term “flux” refers to the quantity of the drugpermeated skin per unit area per unit time. Unless otherwise obviousfrom context, “flux” refers to the arithmetic mean value measured and/orcalculated in accordance with the methods described herein. A typicalunit of flux is milligram per square centimeter per hour.

Flux rate as referenced in this patent application can mean thatmeasured by either in vivo or in vitro methods. One way to measure fluxis to place the transdermal delivery device or formulation on a knownskin area of a human volunteer and measure how much drug can permeateacross skin within certain time constraints. Those skilled in the artwould understand that in some cases, the absolute value of in vitro fluxcan be several fold different when measured using a different cadaversource. As used herein, when specifically referenced as measured by invitro method using human cadaver skin, the flux rate should beunderstood as measured in accordance with the method described inExample 2. For example, a patch tested in Example 2 can be used as areference patch, which when tested in a method in accordance withExample 2, should yield the same flux as observed in Example 2, withinexperimental error generally accepted by those skilled in the art.Although an in vitro method uses human epidermal membrane obtained froma cadaver, rather than measure drug flux across the skin using humanvolunteers, it is generally accepted by those skilled in the art thatresults from a properly designed and executed in vitro test can be usedto estimate or predict the results of an in vivo test with reasonablereliability.

As used herein, the terms “treat,” “treating,” “treatment,” and the likerefer to eliminating, reducing, or ameliorating a disease or condition,and/or symptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated.

The term “therapeutically effective amount,” as used herein, refers tothat amount of a therapeutic agent (e.g., dextromethorphan) sufficientto result in amelioration of one or more symptoms of a disorder orcondition (e.g., PBA), or prevent appearance or advancement of adisorder or condition, or cause regression of or cure from the disorderor condition.

The term “subject” (alternatively referred to herein as “patient”) asused herein, refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

As used herein, applying or administering the transdermal deliverydevice herein should be understood as in accordance with how suchtransdermal delivery device is normally applied or administered, e.g.,to the skin of a human subject.

EXEMPLARY EMBODIMENTS Exemplary Embodiments A1-55

-   -   1. A transdermal delivery device comprising        -   a. an adhesive layer comprising an adhesive, which            optionally comprises dextromethorphan dispersed in the            adhesive in an amount of about 2% to about 12% by weight of            the adhesive layer; and        -   b. a reservoir layer comprising dextromethorphan in an            amount of at least 10% (e.g., about 20% to about 60%) by            weight of the reservoir layer.    -   2. The transdermal delivery device of embodiment A1, wherein the        transdermal delivery device is configured to transdermally        deliver dextromethorphan to a user about 2 mg/day to about 50        mg/day.    -   3. The transdermal delivery device of embodiment A1 or 2,        wherein the transdermal delivery device is configured to        transdermally deliver dextromethorphan to a user about 5 mg/day        to about 50 mg/day (e.g., about 5 mg/day, about 10 mg/day, about        20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, or        any ranges between the recited values) for 1 day or more (e.g.,        1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or any        ranges between the recited values).    -   4. The transdermal delivery device of any one of embodiments        A1-3, which has a total dextromethorphan loading of about 0.5        mg/cm² to about 8 mg/cm².    -   5. The transdermal delivery device of any one of embodiments        A1-4, which has a total dextromethorphan loading of about 2        mg/cm² to about 6 mg/cm² (e.g., about 2 mg/cm², about 3 mg/cm²,        about 4 mg/cm², about 5 mg/cm², about 6 mg/cm², or any ranges        between the recited values).    -   6. The transdermal delivery device of any one of embodiments        A1-5, which has an active surface area of about 5 cm² to about        200 cm²    -   7. The transdermal delivery device of any one of embodiments        A1-6, which has an active surface area of about 10 cm² to about        150 cm²    -   8. The transdermal delivery device of any one of embodiments        A1-7, which has an active surface area of about 30 cm² to about        100 cm² (e.g., about 30 cm², about 40 cm², about 50 cm², about        60 cm², about 70 cm², about 80 cm², about 90 cm², about 100 cm²,        or any ranges between the recited values).    -   9. The transdermal delivery device of any one of embodiments        A1-8, wherein the adhesive layer comprises dextromethorphan in        an amount of about 6% to about 12% (e.g., about 6%, about 7%,        about 8%, about 9%, about 10%, about 11%, about 12%, or any        ranges between the recited values) by weight of the adhesive        layer.    -   10. The transdermal delivery device of any one of embodiments        A1-9, wherein the adhesive layer further comprises a skin        permeation enhancer.    -   11. The transdermal delivery device of embodiment A10, wherein        the skin permeation enhancer is selected from isopropyl        myristate, oleyl oleate, oleic acid, glycerol monooleate, other        fatty acids and fatty acid esters with carbon chain lengths of        C₁₂ to C₁₈, and combinations thereof.    -   12. The transdermal delivery device of embodiment A10 or 11,        wherein the skin permeation enhancer is present in an amount of        about 2% to about 15% by weight of the adhesive layer.    -   13. The transdermal delivery device of any one of embodiments        A10-12, wherein the skin permeation enhancer is present in an        amount of about 6% to about 12% (e.g., about 6%, about 7%, about        8%, about 9%, about 10%, about 11%, about 12%, or any ranges        between the recited values) by weight of the adhesive layer.    -   14. The transdermal delivery device of any one of embodiments        A1-13, wherein the adhesive layer further comprises an agent to        improve cohesive strength of the adhesive layer.    -   15. The transdermal delivery device of any one of embodiments        A1-13, wherein the adhesive layer further comprises an agent        selected from a vinylpyrrolidone polymer (e.g., a        vinylpyrrolidone-vinyl acetate copolymers), Kollidon (e.g.,        Kollidon 30 LP, Kollidon 90, or Kollidon VA64), silicone        dioxide, titanium dioxide, and combinations thereof.    -   16. The transdermal delivery device of embodiment A14 or 15,        wherein the agent is present in an amount of about 1% to about        20% by weight of the adhesive layer.    -   17. The transdermal delivery device of any one of embodiments        A14-16, wherein the agent is present in an amount of about 2% to        about 20% (e.g., about 2%, about 2.5%, about 3%, about 4%, about        5%, about 6%, about 10%, about 15%, about 20%, or any ranges        between the recited values), for example, about 2% to about 6%        (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, or        any ranges between the recited values) by weight of the adhesive        layer.    -   18. The transdermal delivery device of any one of embodiments        A1-17, wherein the adhesive comprises a pressure sensitive        adhesive.    -   19. The transdermal delivery device of embodiment A18, wherein        the pressure sensitive adhesive comprises a polyisobutylene        adhesive, a silicone polymer adhesive, an acrylate copolymer        adhesive (e.g., a poly acrylate vinyl acetate copolymer, such as        Duro-Tak 87-2287), or a combination thereof.    -   20. The transdermal delivery device of embodiment A18 or 19,        wherein the pressure sensitive adhesive is present in an amount        of about 50% to about 90% by weight of the adhesive layer.    -   21. The transdermal delivery device of any one of embodiments        A18-20, wherein the pressure sensitive adhesive is present in an        amount of about 60% to about 85% (e.g., about 60%, about 70%,        about 75%, about 80%, about 85%, or any ranges between the        recited values) by weight of the adhesive layer.    -   22. The transdermal delivery device of any one of embodiments        A1-21, wherein the adhesive layer is capable of adhering to a        user's skin continuously for at least 1 day (e.g., at least 2        days, at least 3 days, at least 4 days, at least 5 days, at        least 6 days, at least 7 days).    -   23. The transdermal delivery device of any one of embodiments        A1-22, wherein the adhesive layer is about 0.1 mil to about 10        mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to        10 mils).    -   24. The transdermal delivery device of any one of embodiments        A1-23, wherein the reservoir layer comprises dextromethorphan in        an amount of about 30% to about 50% (e.g., about 30%, about 35%,        about 40%, about 45%, about 50%, or any ranges between the        recited values) by weight of the reservoir layer.    -   25. The transdermal delivery device of any one of embodiments        A1-24, wherein the reservoir layer further comprises a skin        permeation enhancer.    -   26. The transdermal delivery device of embodiment A25, wherein        the skin permeation enhancer is selected from isopropyl        myristate, oleyl oleate, oleic acid, glycerol monooleate, other        fatty acids and fatty acid esters with carbon chain lengths of        C₁₂ to C₁₈, and combinations thereof.    -   27. The transdermal delivery device of embodiment A25 or 26,        wherein the skin permeation enhancer is present in an amount of        about 2% to about 15% by weight of the reservoir layer.    -   28. The transdermal delivery device of any one of embodiments        A25-27, wherein the skin permeation enhancer is present in an        amount of about 6% to about 12% (e.g., about 6%, about 7%, about        8%, about 9%, about 10%, about 11%, about 12%, or any ranges        between the recited values) by weight of the reservoir layer.    -   29. The transdermal delivery device of any one of embodiments        A1-28, wherein the reservoir layer further comprises an agent to        improve cohesive strength of the reservoir layer.    -   30. The transdermal delivery device of any one of embodiments        A1-28, wherein the reservoir layer further comprises an agent        selected from a vinylpyrrolidone polymer (e.g., a        vinylpyrrolidone-vinyl acetate copolymers), Kollidon (e.g.,        Kollidon 30 LP, Kollidon 90, or Kollidon VA64), silicone        dioxide, titanium dioxide, and combinations thereof.    -   31. The transdermal delivery device of embodiment A29 or 30,        wherein the agent is present in an amount of about 1% to about        20% by weight of the reservoir layer.    -   32. The transdermal delivery device of any one of embodiments        A29-31, wherein the agent is present in an amount of about 2% to        about 20% (e.g., about 2%, about 2.5%, about 3%, about 4%, about        5%, about 6%, about 10%, about 15%, about 20%, or any ranges        between the recited values), for example, about 2% to about 6%        (e.g., about 2%, about 2.5%, about 3%, about 4%, about 5%, or        any ranges between the recited values) by weight of the        reservoir layer.    -   33. The transdermal delivery device of any one of embodiments        A1-32, wherein the reservoir layer comprises dextromethorphan        dispersed, e.g., homogenously dispersed, in a pressure sensitive        adhesive.    -   34. The transdermal delivery device of embodiment A33, wherein        the pressure sensitive adhesive comprises a polyisobutylene        adhesive, a silicone polymer adhesive, an acrylate copolymer        adhesive (e.g., a poly acrylate vinyl acetate copolymer, such as        Duro-Tak 87-2287), or a combination thereof.    -   35. The transdermal delivery device of embodiment A33 or 34,        wherein the pressure sensitive adhesive is present in an amount        of about 20% to about 80% by weight of the reservoir layer.    -   36. The transdermal delivery device of any one of embodiments        A33-35, wherein the pressure sensitive adhesive is present in an        amount of about 20% to about 65% (e.g., about 20%, about 30%,        about 35%, about 40%, about 50%, about 60%, about 65%, or any        ranges between the recited values) by weight of the reservoir        layer.    -   37. The transdermal delivery device of any one of embodiments        A1-36, wherein the reservoir layer is about 0.1 mil to about 10        mils thick (e.g., about 0.5 mil to about 10 mils, about 1 mil to        about 10 mils).    -   38. The transdermal delivery device of any one of embodiments        A1-37, wherein the adhesive layer and reservoir layer are        separated by a rate-controlling membrane.    -   39. A method of administering dextromethorphan to a subject in        need thereof, the method comprising applying the transdermal        delivery device of any one of embodiments A1-38 or C1-21 to the        subject, or the method comprising applying to the subject a        transdermal delivery device comprising an adhesive layer having        the same or substantially the same ingredients as in Formulation        A, B, C1, C2, C3, D0, D1, or D2 in the Examples.    -   40. The method of embodiment A39, wherein the subject does not        suffer from a cough and/or does not need an antitussive.    -   41. The method of embodiment A39 or 40, wherein the subject is        characterized as an extensive metabolizer.    -   42. The method of any one of embodiments A39-41, wherein the        subject suffers from a neurological disease or disorder.    -   43. The method of any one of embodiments A39-41, wherein the        subject suffers from one or more diseases or disorders selected        from affective disorders, psychiatric disorders, cerebral        function disorders, movement disorders, dementias, motor neuron        diseases, neurodegenerative diseases, seizure disorders, and        headaches.    -   44. The method of any one of embodiments A39-41, wherein the        subject suffers from one or more diseases or disorders selected        from depression, major depression, treatment resistant        depression, treatment resistant bipolar depression, bipolar        disorders including cyclothymia, seasonal affective disorder,        mood disorders, chronic depression (dysthymia), psychotic        depression, postpartum depression, premenstrual dysphoric        disorder (PMDD), situational depression, atypical depression,        mania, anxiety disorders, attention deficit disorder (ADD),        attention deficit disorder with hyperactivity (ADDH), attention        deficit/hyperactivity disorder (AD/HD), bipolar and manic        conditions, obsessive-compulsive disorder, bulimia, obesity or        weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual        syndrome, substance addiction or abuse, nicotine addiction,        psycho-sexual dysfunction, pseudobulbar affect, and emotional        lability.    -   45. The method of any one of embodiments A39-41, wherein the        subject suffers from one or more diseases or disorders selected        from Alzheimer's disease, prion-related diseases, cerebellar        ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy        (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's        disease, Lewy body disease, Parkinson's disease, amyotrophic        lateral sclerosis (ALS or Lou Gehrig's disease), multiple        sclerosis (MS), multiple system atrophy, Shy-Drager syndrome,        corticobasal degeneration, progressive supranuclear palsy,        Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral        autosomal dominant arteriopathy with subcortical infarcts and        leukoencephalopathy (CADASIL), muscular dystrophies,        Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis,        neurofibromatosis, olivopontine cerebellar atrophy or        degeneration, striatonigral degeneration, Guillain-Barré        syndrome, and spastic paraplesia.    -   46. The method of any one of embodiments A39-41, wherein the        subject suffers from pseudobulbar affect, depression, stroke,        traumatic brain injury, seizure, pain (e.g., post-operative        pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's        disease, autism, or combinations thereof.    -   47. The method of any one of embodiments A39-46, further        comprising administering to the subject an antidepressant.    -   48. The method of embodiment A47, wherein the antidepressant is        selected from bupropion, hydroxybupropion,        erythrohydroxybupropion, threohydroxybupropion, a metabolite or        prodrug of any of these compounds, and combinations thereof.    -   49. The method of any one of embodiments A39-46, further        comprising administering to the subject quinidine.    -   50. The method of any one of embodiments A39-46, wherein the        subject is not administered a CYP2D6 inhibitor.    -   51. The method of any one of embodiments A39-46, wherein the        subject is not administered quinidine.    -   52. The method of any one of embodiments A39-46, wherein the        subject is not administered any of desipramine, paroxetine,        thioridazine, pimozide, digoxin, atazanavir, clarithromycin,        indinavir, itraconazole, ketoconazole, and combinations thereof.    -   53. The method of any one of embodiments A39-46, further        comprising administering to the subject one or more additional        active agents selected from amlodipine, a capsaicinoid (e.g.,        capsaicin or an ester thereof), an opioid agonist (e.g., a        μ-opiate analgesic (e.g., tramadol)), an adenosinergic agonist,        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, gabapentin,        and pharmaceutically acceptable salts thereof.    -   54. The method of any one of embodiments A39-53, wherein the        transdermal delivery device is applied once daily, e.g., for a        period of up to 7 days or more, or for at least 7 days or any        desired period of time.    -   55. The method of any one of embodiments A39-53, wherein the        transdermal delivery device is applied once a week or 2, 3, 4,        5, or 6 times a week.

Exemplary Embodiments B1-26

-   -   1. A method of administering dextromethorphan to a human subject        in need thereof, the method comprising applying a transdermal        delivery device comprising dextromethorphan to the skin of the        subject once daily, wherein the applying results in one or more        of the following pharmacokinetic profile in the human subject:        -   a. a mean C_(max) of dextromethorphan of at least about 3            ng/ml (e.g., about 3 ng/ml to about 12 ng/ml) at day 1 post            application;        -   b. a mean AUC₀₋₂₄ of dextromethorphan of at least about 40            ng*h/ml (e.g., about 40 ng*h/ml to about 150 ng*h/ml) at day            1 post application;        -   c. a mean ratio of C_(24h)/C_(12h) of dextromethorphan of            not more than about 1.5 (e.g., about 1 to about 1.5) at day            1 post application;        -   d. a mean ratio of C_(24h)/C_(6h) of dextromethorphan of at            least about 1.2 (e.g., about 1.5 to about 2.5) at day 1 post            application;        -   e. a mean ratio of C_(24h)/C_(18h) of dextromethorphan of            about 0.85 to about 1.3 at day 1 post application;        -   f. a mean C_(max) of dextrorphan of not more than 2 ng/ml            (e.g., not more than 2 ng/ml, not more than 1 ng/ml, or not            more than 0.5 ng/ml) at day 1 post application;        -   g. a mean AUC₀₋₂₄ of dextrorphan of not more than 10 ng*h/ml            (e.g., not more than 10 ng*h/ml or not more than 5 ng*h/ml)            at day 1 post application;        -   h. a mean ratio of C_(max) of dextromethorphan to C_(max) of            dextrophan of at least about 5 (e.g., at least about 10, at            least about 15, at least about 20) at day 1 post            application; and        -   i. a mean ratio of AUC₀₋₂₄ of dextromethorphan to AUC₀₋₂₄ of            dextrophan of at least about 5 (e.g., at least about 10, at            least about 15, at least about 20, or at least about 25) at            day 1 post application.    -   2. The method of embodiment B1, wherein the human subject does        not suffer from a cough and/or does not need an antitussive.    -   3. The method of embodiment B1 or 2, wherein the human subject        is characterized as an extensive metabolizer.    -   4. The method of any one of embodiments B1-3, wherein the        applying results in a mean C_(max) of dextromethorphan of at        least about 30% (e.g., about 30% to about 80%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject, when measured at day 1 post application.    -   5. The method of any one of embodiments B1-4, wherein the        applying results in a mean AUC₀₋₂₄ of dextromethorphan of at        least about 30% (e.g., about 30% to about 80%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject, when measured at day 1 post application.    -   6. The method of any one of embodiments B1-5, wherein the        applying results in a mean C_(max) of dextrorphan of not more        than about 50% (e.g., about 10% to about 30%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject, when measured at day 1 post application.    -   7. The method of any one of embodiments B1-6, wherein the        applying results in a mean AUC₀₋₂₄ of dextrorphan of not more        than about 50% (e.g., about 10% to about 30%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject, when measured at day 1 post application.    -   8. The method of any one of embodiments B1-7, wherein the human        subject suffers from pseudobulbar affection, depression, stroke,        traumatic brain injury, seizure, pain (e.g., post-operative        pain, neuropathic pain), methotrexate neurotoxicity, Parkinson's        disease, autism, or a combination thereof.    -   9. The method of anyone of embodiments B1-8, comprising applying        the transdermal delivery device once a day for a period of time        up to seven days or for at least 7 days or any desired period of        time, wherein the applying results in one or both of the        following pharmacokinetic profile in the human subject:        -   a. a mean C_(max) of dextromethorphan of at least about 8            ng/ml (e.g., about 8 ng/ml to about 20 ng/ml) at day 7 post            application; and        -   b. a mean C_(max) of dextrorphan of not more than 2 ng/ml            (e.g., e.g., not more than 2 ng/ml, not more than 1 ng/ml,            or not more than 0.5 ng/ml) at day 7 post application.    -   10. The method of anyone of embodiments B1-9, wherein the        transdermal delivery device comprises about 5 mg to about 100 mg        of dextromethorphan.    -   11. A method of administering dextromethorphan to a human        subject in need thereof, the method comprising applying a        transdermal delivery device comprising dextromethorphan to the        skin of the subject once a week or 2, 3, 4, 5, or 6 times a        week, wherein the applying results in one or more of the        following pharmacokinetic profile in the human subject:        -   a. a mean C_(max) of dextromethorphan of at least about 3            ng/ml (e.g., about 3 ng/ml to about 12 ng/ml) at day 1 post            application;        -   b. a mean AUC₀₋₂₄ of dextromethorphan of at least about 40            ng*h/ml (e.g., about 40 ng*h/ml to about 150 ng*h/ml) at day            1 post application;        -   c. a mean ratio of C_(24h)/C_(12h) of dextromethorphan of            not more than about 1.5 (e.g., about 1 to about 1.5) at day            1 post application;        -   d. a mean ratio of C_(24h)/C_(6h) of dextromethorphan of at            least about 1.2 (e.g., about 1.5 to about 2.5) at day 1 post            application;        -   e. a mean ratio of C_(24h)/C_(18h) of dextromethorphan of            about 0.85 to about 1.3 at day 1 post application;        -   f. a mean C_(max) of dextrorphan of not more than 2 ng/ml            (e.g., not more than 2 ng/ml, not more than 1 ng/ml, or not            more than 0.5 ng/ml) at day 1 post application;        -   g. a mean AUC₀₋₂₄ of dextrorphan of not more than 10 ng*h/ml            (e.g., not more than 10 ng*h/ml or not more than 5 ng*h/ml)            at day 1 post application;        -   h. a mean ratio of C_(max) of dextromethorphan to C_(max) of            dextrophan of at least about 5 (e.g., at least about 10, at            least about 15, at least about 20) at day 1 post            application; and        -   i. a mean ratio of AUC₀₋₂₄ of dextromethorphan to AUC₀₋₂₄ of            dextrophan of at least about 5 (e.g., at least about 10, at            least about 15, at least about 20, or at least about 25) at            day 1 post application.    -   12. The method of embodiment B11, wherein the applying further        results in one or both of the following pharmacokinetic profile        in the human subject:        -   a. a mean C_(max) of dextromethorphan of at least about 8            ng/ml (e.g., about 8 ng/ml to about 20 ng/ml) at day 7 post            application; and        -   b. a mean C_(max) of dextrorphan of not more than 2 ng/ml            (e.g., e.g., not more than 2 ng/ml, not more than 1 ng/ml,            or not more than 0.5 ng/ml) at day 7 post application.    -   13. The method of embodiment B11 or 12, wherein the human        subject does not suffer from a cough and/or does not need an        antitussive.    -   14. The method of any one of embodiments B11-13, wherein the        human subject is characterized as an extensive metabolizer.    -   15. The method of any one of embodiments B11-14, wherein the        applying results in a mean C_(max) of dextromethorphan of at        least about 30% (e.g., about 30% to about 80%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject for 7 days, when measured at day 7 post application.    -   16. The method of any one of embodiments B11-15, wherein the        applying results in a mean AUC₀₋₂₄ of dextromethorphan of at        least about 30% (e.g., about 30% to about 80%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject for 7 days, when measured at day 7 post application.    -   17. The method of any one of embodiments B11-16, wherein the        applying results in a mean C_(max) of dextrorphan of not more        than about 50% (e.g., about 10% to about 30%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject for 7 days, when measured at day 7 post application.    -   18. The method of any one of embodiments B11-17, wherein the        applying results in a mean AUC₀₋₂₄ of dextrorphan of not more        than about 50% (e.g., about 10% to about 30%) of that observed        from orally administering a combination of 20 mg        dextromethorphan and 10 mg quinidine twice a day to the human        subject for 7 days, when measured at day 7 post application.    -   19. The method of any one of embodiments B11-18, wherein the        human subject suffers from pseudobulbar affection.    -   20. The method of anyone of embodiments B11-19, wherein the        transdermal delivery device comprises about 50 mg to about 700        mg of dextromethorphan.    -   21. A method of treating a disease or disorder in a subject in        need thereof, the method comprising administering a transdermal        delivery device comprising dextromethorphan to the skin of the        subject once daily, wherein the applying results in one or more        of the pharmacokinetic profile recited in embodiments B1, B3-7        and B9, wherein the disease or disorder is any of those        described herein.    -   22. The method of embodiment 21, wherein the disease or disorder        is a neurological disease or disorder, e.g., pseudobulbar        affection.    -   23. A method of treating a disease or disorder in a subject in        need thereof, the method comprising administering a transdermal        delivery device comprising dextromethorphan to the skin of the        subject once a week or 2, 3, 4, 5, or 6 times a week, wherein        the applying results in one or more of the pharmacokinetic        profile recited in embodiments B11-12 and B15-18, wherein the        disease or disorder is any of those described herein.    -   24. The method of embodiment 21, wherein the disease or disorder        is a neurological disease or disorder, e.g., pseudobulbar        affection.    -   25. The method of any one of embodiments B1-24, wherein the        transdermal delivery device is selected from the transdermal        delivery device of any of embodiments A1-38 and C1-21.    -   26. The method of any one of embodiments B1-24, wherein the        transdermal delivery device comprises an adhesive layer having        the same or substantially the same ingredients as in Formulation        A, B, C1, C2, C3, D0, D1, or D2 in the Examples.

Exemplary Embodiments C1-32

-   -   1. A transdermal delivery device comprising:        -   an adhesive layer comprising dextromethorphan dispersed in            an adhesive comprising        -   an acrylate adhesive and a silicone adhesive,        -   wherein the weight ratio of the acrylate adhesive to silicon            adhesive ranges from about 20:1 to about 1:20.    -   2. The transdermal delivery device of embodiment C1, wherein the        weight ratio of the acrylate adhesive to silicon adhesive ranges        from about 10:1 to about 1:10 (e.g., about 10:1, about 4:1,        about 1:1, about 1:4, or any ranges between the recited value).    -   3. The transdermal delivery device of embodiment C1 or 2, which        is configured to provide a mean cumulative dextromethorphan        permeated of at least about 200 ug/cm² (e.g., about 200 ug/cm²        to about 2000 ug/cm²) at 24 hours post application, when tested        in vitro using human cadaver skin.    -   4. The transdermal delivery device of any one of embodiments        C1-3, which is configured to provide a mean average flux of        dextromethorphan of at least about 5 ug/cm²*h (e.g., about 5        ug/cm²*h to about 20 ug/cm²*h, about 10 ug/cm²*h to about 18        ug/cm²*h) from 8 hours to 24 hours post application, when tested        in vitro using human cadaver skin.    -   5. The transdermal delivery device of any one of embodiments        C1-4, wherein the adhesive layer further comprises a skin        permeation enhancer in an amount to provide a mean cumulative        dextromethorphan permeated at 24 hours post application of at        least about 25% (e.g., about 25%, about 50%, about 100%, about        150%, about 200%, or any ranges between the recited value)        higher than that of an otherwise equivalent transdermal delivery        device without the skin permeation enhancer, when tested in        vitro using human cadaver skin.    -   6. The transdermal delivery device of anyone of embodiments        C1-5, wherein the adhesive layer comprises a skin permeation        enhancer in an amount to provide a mean average flux of        dextromethorphan from 8 hours to 24 hours post application of at        least about 25% (e.g., about 25%, about 50%, about 100%, about        150%, about 200%, or any ranges between the recited value)        higher than that of an otherwise equivalent transdermal delivery        device without the skin permeation enhancer, when tested in        vitro using human cadaver skin.    -   7. The transdermal delivery device of any one of embodiments        C1-6, wherein the adhesive layer comprises a skin permeation        enhancer in an amount to provide a mean average flux of        dextromethorphan from 4 hours to 8 hours post application of at        least about 2-fold (e.g., about 3-fold, about 4-fold, about        5-fold, about 8-fold, about 10-fold, or any ranges between the        recited value) of that of an otherwise equivalent transdermal        delivery device without the skin permeation enhancer, when        tested in vitro using human cadaver skin.    -   8. The transdermal delivery device of any one of embodiments        C1-7, wherein the adhesive layer comprises a skin permeation        enhancer in an amount to provide a mean average flux of        dextromethorphan from 0 hours to 4 hours post application of at        least about 5-fold (e.g., about 5-fold, about 8-fold, about        10-fold, about 20-fold, or any ranges between the recited value)        of that of an otherwise equivalent transdermal delivery device        without the skin permeation enhancer, when tested in vitro using        human cadaver skin.    -   9. The transdermal delivery device of any one of embodiments        C1-8, which is suitable for 1-day, 2-day, 3-day, 4-day, 5-day,        6-day, or 7-day application.    -   10. The transdermal delivery device of embodiment C9, which is        configured to provide dextromethorphan to a user of at least        about 200 ug/cm² (e.g., about 200 ug/cm² to about 2000 ug/cm²)        per day.    -   11. The transdermal delivery device of any one of embodiments        C1-10, which has a size of about 5 cm² to about 200 cm².    -   12. The transdermal delivery device of any one of embodiments        C1-11, which has a size of about 10 cm² to about 100 cm².    -   13. A transdermal delivery device comprising:        -   an adhesive layer comprising dextromethorphan dispersed in            an adhesive,        -   wherein the adhesive layer comprises a skin permeation            enhancer in an amount to provide a mean cumulative            dextromethorphan permeated at 24 hours post application of            at least about 25% (e.g., about 25%, about 50%, about 100%,            about 150%, about 200%, or any ranges between the recited            value) higher than that of an otherwise equivalent            transdermal delivery device without the skin permeation            enhancer, when tested in vitro using human cadaver skin.    -   14. The transdermal delivery device of embodiment C13, wherein        the skin permeation enhancer is in an amount to provide a mean        average flux of dextromethorphan from 8 hours to 24 hours post        application of at least about 25% (e.g., about 25%, about 50%,        about 100%, about 150%, about 200%, or any ranges between the        recited value) higher than that of an otherwise equivalent        transdermal delivery device without the skin permeation        enhancer, when tested in vitro using human cadaver skin.    -   15. The transdermal delivery device of embodiment C13 or 14,        wherein the skin permeation enhancer is in an amount to provide        a mean average flux of dextromethorphan from 4 hours to 8 hours        post application of at least about 2-fold (e.g., about 3-fold,        about 4-fold, about 5-fold, about 8-fold, about 10-fold, or any        ranges between the recited value) of that of an otherwise        equivalent transdermal delivery device without the skin        permeation enhancer, when tested in vitro using human cadaver        skin.    -   16. The transdermal delivery device of any one of embodiments        C13-15, wherein the skin permeation enhancer is in an amount to        provide a mean average flux of dextromethorphan from 0 hours to        4 hours post application of at least about 5-fold (e.g., about        5-fold, about 8-fold, about 10-fold, about 20-fold, or any        ranges between the recited value) of that of an otherwise        equivalent transdermal delivery device without the skin        permeation enhancer, when tested in vitro using human cadaver        skin.    -   17. The transdermal delivery device of any one of embodiments        C13-16, which is suitable for 1-day, 2-day, 3-day, 4-day, 5-day,        6-day, or 7-day application.    -   18. The transdermal delivery device of embodiment C17, which is        configured to provide dextromethorphan to a user of at least        about 200 ug/cm² (e.g., about 200 ug/cm² to about 2000 ug/cm²)        per day.    -   19. The transdermal delivery device of any one of embodiments        C13-18, which has a size of about 5 cm² to about 200 cm².    -   20. The transdermal delivery device of any one of embodiments        C13-19, which has a size of about 10 cm² to about 100 cm².    -   21. The transdermal delivery device of any one of embodiments        C13-20, wherein the skin permeation enhancer is selected from        isopropyl myristate, oleyl oleate, oleic acid, glycerol        monooleate, other fatty acids and fatty acid esters with carbon        chain lengths of C₁₂ to C₁₈, and combinations thereof.    -   22. A method of administering dextromethorphan to a subject in        need thereof, the method comprising applying a transdermal        delivery device to the skin of the subject, wherein the        transdermal delivery device comprises an adhesive layer, wherein        the adhesive layer comprises dextromethorphan dispersed in an        adhesive, and a skin permeation enhancer, wherein the skin        permeation enhancer is in an amount such that the applying        results in a mean cumulative dextromethorphan permeated at 24        hours post application of at least about 25% (e.g., about 25%,        about 50%, about 100%, about 150%, about 200%, or any ranges        between the recited value) higher than that from applying an        otherwise equivalent transdermal delivery device without the        skin permeation enhancer.    -   23. The method of embodiment C22, wherein the skin permeation        enhancer is in an amount such that the applying results in a        mean average flux of dextromethorphan from 8 hours to 24 hours        post application of at least about 25% (e.g., about 25%, about        50%, about 100%, about 150%, about 200%, or any ranges between        the recited value) higher than that from applying an otherwise        equivalent transdermal delivery device without the skin        permeation enhancer.    -   24. The method of embodiment C22 or 23, wherein the skin        permeation enhancer is in an amount such that the applying        results in a mean average flux of dextromethorphan from 4 hours        to 8 hours post application of at least about 2-fold (e.g.,        about 3-fold, about 4-fold, about 5-fold, about 8-fold, about        10-fold, or any ranges between the recited value) of that from        applying an otherwise equivalent transdermal delivery device        without the skin permeation enhancer.    -   25. The method of any one of embodiments C22-24, wherein the        skin permeation enhancer is in an amount such that the applying        results in a mean average flux of dextromethorphan from 0 hours        to 4 hours post application of at least about 5-fold (e.g.,        about 5-fold, about 8-fold, about 10-fold, about 20-fold, or any        ranges between the recited value) of that from applying an        otherwise equivalent transdermal delivery device without the        skin permeation enhancer.    -   26. The method of any one of embodiments C22-25, wherein the        transdermal delivery device is applied once a day for 1 day or        more, (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7        days, or more).    -   27. The method of embodiment C26, which transdermally delivers        dextromethorphan to the subject at least about 200 ug/cm² (e.g.,        about 200 ug/cm² to about 2000 ug/cm²) per day.    -   28. The method of any one of embodiments C22-27, wherein the        transdermal delivery device has a size of about 5 cm² to about        200 cm².    -   29. The method of any one of embodiments C22-28, wherein the        transdermal delivery device has a size of about 10 cm² to about        100 cm².    -   30. The method of any one of embodiments C22-29, wherein the        skin permeation enhancer is selected from isopropyl myristate,        oleyl oleate, oleic acid, glycerol monooleate, other fatty acids        and fatty acid esters with carbon chain lengths of C₁₂ to C₁₈,        and combinations thereof.    -   31. A method of administering dextromethorphan to a subject in        need thereof, the method comprising applying a transdermal        delivery device to the skin of the subject, wherein the        transdermal delivery device is configured to have a flux        characteristic such that the applying transdermally delivers        dextromethorphan about 2 mg/day to about 50 mg/day to the        subject.    -   32. The method of embodiment C31, wherein the transdermal        delivery device is configured to have a flux characteristic such        that the applying transdermally delivers dextromethorphan about        5 mg/day to about 50 mg/day (e.g., about 5 mg/day, about 10        mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about        50 mg/day, or any ranges between the recited values) to the        subject for 1 day or more (e.g., 1.5 days, 2 days, 3 days, 4        days, 5 days, 6 days, 7 days, or any ranges between the recited        values).

EXAMPLES Example 1. Preparation of Dextromethorphan Transdermal Patch

This example shows one procedure for preparing dextromethorphandrug-in-adhesive patch. Dextromethorphan base is generally commerciallyavailable. Alternatively, dextromethorphan base can be prepared byconversion of dextromethorphan hydrobromide into the free base, forexample, using a 1:1 molar ratio of NaOH.

Preparation of Formulation A, which uses acrylate adhesive with no skinpermeation enhancers. In a 150-mL beaker was added in 10 g of ethylacetate, followed by 2.5 g of DXM. The blend was mixed to dissolve theDXM. While mixing, it was added in acrylic PSA, 50 g of DuroTak 87-2287(Henkel Adhesives) which has 50.5% of solids. Mixed the batch contentfor 30 minutes or till the content is homogeneous. The resulting wetsolution was then casted onto a release liner (Loparex Corp.), using acasting applicator of 10 mils. The casting was dried in a forced-airoven at 80° C. for 10 min. After drying, the dried casting was laminatedto a patch backing film, Scotchpak 1012 (3 M Drug Delivery Systems). Thepatch was die-cut into a 30 cm² shape. The resulting transdermal patchhas adhesive matrix thickness of 2.5 mils (weighs about 180 mg ofadhesive matrix per patch), and contains 9% DXM. HPLC analysis confirmedthat a patch contains about 16 mg of DXM. The patch has good skinadhesion and adhered snugly on skin for more than 48 hours. The patchwas die-cut to fix on the Franz cells for skin permeation study. Nocrystals were observed on the patch for 6 months at 25° C., indicatinggood stability of the transdermal patch formulation.

Preparation of Formulation B, which uses silicone adhesive with no skinpermeation enhancers. In a 150-mL beaker was added in 10 g of ethylacetate, followed by 2.5 g of DXM. The blend was mixed to dissolve theDXM. While mixing, it was added in silicone PSA, 50 g of Bio-PSADC7-4502 (Dow Corning) which has 60.0% of solids. The batch content wasmixed for 30 minutes or till the content is homogeneous. The resultingwet solution was casted onto a fluoropolymer-coated release liner (3M's1022) using a casting applicator of 15 mils. The casting was dried in aforced-air oven at 80° C. for 10 min. After drying, the dried castingwas laminated to a patch backing film, Scotchpak 1012 (3 M Drug DeliverySystems). The patch was die-cut into a 30 cm2 shape. The resultingtransdermal patch has adhesive matrix thickness of 3.5 mils. The patchhas good skin adhesion and adhered snugly on skin for more than 48hours. The patch was die-cut to fix on the Franz cells for skinpermeation study. No crystals were observed on the patch for 6 months at25° C., indicating good stability of the transdermal patch formulation.

Preparation of Formulation C, which uses a mixture of acrylate andsilicone adhesive with no skin permeation enhancers, with theconcentration of dextromethorphan being kept 9%. Following similarprocedures above, three formulations were prepared, Formulation C1-C3,with a blend of silicone/acrylic PSA at a ratio of 54/46, 18/82, and9/91, respectively.

Preparation of Formulation D, Following similar procedures above,formulations with various amounts of permeation enhancers are alsoprepared. Formulation D1 contains isopropyl myristate in an amount of7.7%; Formulation D2 contains isopropyl myristate in an amount of 10%.As a control, Formulation D0 was also prepared, which contains noisopropyl myristate.

The following table 1 summarizes the ingredients of differentformulations prepared above, with weight percentages. (The percentagesin the table refers to dry weight.)

TABLE 1 Formulation No. A B C1 C2 C3 D0 D1 D2 DXM 9 8 9 9 9 10 10 10DuroTak 87-2287 91 92 49 16 8 90 82.3 80 DC 7-4502 42 75 83 IPM 0 7.7 10Total 100 100 100 100 100 100 100 100

Example 2. Transdermal Flux Test

Transdermal flux of Dextromethorphan from the patch was tested usinghuman cadaver epidermis by Franz Diffusion Cell method.

Patch formulations A, B, and C prepared in Example 1 were used for askin permeation study using the following protocol:

-   -   Franz cell assembly—Logan Instruments (6-cell unit)    -   Each cell has 12 mL volume, 1.5 cm diameter orifice    -   Receptor medium is a phosphate buffer solution (PBS) pH 7.4    -   Cell temperature is maintained at 37° C.    -   Sampling method: take 1.5 mL for HPLC assay, empty cell, replace        with fresh medium    -   Sampling time points: 4, 8, 12, 24 and 48 hours    -   Cadaver skin is used and is obtained from New York Fire Fighters        Skin Bank. Skin No. MM07116, While, Age 58, male, skin site:        left posterior leg.    -   Assay method for media: HPLC based.

RESULTS of the study for Formulations A and B are presented in Table 1below (See also FIG. 1). The values presented are cumulative amount ofDXM permeated per cm² (i.e., μg/cm²).

TABLE 2 Formulation A B Acrylic PSA Silicone PSA Hours DuroTak 87-2287DC7-4502 0 0.0 0.0 4 48.6 25.8 8 124.9 79.8 12 201.3 138.1 24 424.3294.4 48 625.1 597.0

RESULTS of the study for Formulations C1-C3 are presented in Table 3below (See also FIG. 2). The values presented are cumulative amount ofDXM permeated per cm² (i.e., μg/cm²).

TABLE 3 Formulation C1 C2 C3 Day/Sil:Acrylic ratio 54/46 18/82 9/91 0.3371.0 34.8 159.5 1 308.1 215.9 487.0 2 536.5 433.3 768.8 3 667.8 584.1902.6 4 755.2 703.7 979.1 5 815.8 784.0 1023.5 6 866.3 854.6 1060.6 7906.7 910.2 1086.1

Example 3. Dextromethorphan Transdermal Patch with Permeation Enhancers

Formulations D0-D2 were also tested for their in vitro fluxcharacteristics following the same protocol as described in Example 2.The results were shown in Table 4 (see also FIG. 3).

TABLE 4 Formulation D0 D1 D2 IPM % 0 7.7 10.0 24-h flux 141.3 240.0334.6

The results clearly indicate that increased level of IPM, up to 10%,significantly enhance the skin permeation of DXM.

Example 4. In Vivo Pharmacokinetic Studies

This example concerns an open-label, randomized, two-treatment,two-period, two-sequence crossover study that was conducted with 16healthy adult male and female subjects to evaluate the comparativebioavailability of a test dextromethorphan patch, 15 mg/24 hr relativeto that of NUEDEXTA® (dextromethorphan hydrobromide and quinidinesulfate) capsules, 20 mg/10 mg (Avanir Pharmaceuticals, Inc.) underfasted conditions. The 16 subjects in this study were all genotyped todetermine CYP2D6 genotype. All 16 subjects can be characterized asdextromethorphan extensive metabolizer. See e.g., Treducu A. L. D. etal. Frontiers in Pharmacology, vol. 9, Article 305 (April 2018).

The pharmacokinetic profile for both dextromethorphan and dextrorphan(one metabolite of dextromethorphan) were measured in this study.

In one period of the study, one (1) dextromethorphan patch, a 45 cm²patch with 35 mg DXM, which is a drug-in-adhesive patch, with the DIAlayer containing about 80% by weight of an adhesive (Duro-Tak 87-2287),about 10% by weight of dextromethorphan base and about 10% by weight ofpermeation enhancer isopropyl myristate, which was designed totransdermally deliver about 15 mg/24 hr, was applied on the upper outerleft arm of healthy subjects for 24 hours following an overnight fast ofat least 10 hours. In the other study period, a single NUEDEXTA®(dextromethorphan hydrobromide and quinidine sulfate) capsule, 20 mg/10mg, was administered every 12 hours (0 and 12 hours) (for a total doseof 40 mg/20 mg over a 24-hour period) following an overnight fast of atleast 10 hours (0-hour).

For NUEDEXTA® treatment, the subjects were overnight fasted of at least10 hours only prior to the 0-hour dose. The order of administrationfollows a two-sequence randomization schedule. Blood samples werecollected pre-dose and at intervals over 96 hours after dosing (0-hour)with the study drug in each study period. Subjects were confined at theclinical facility from at least 10 hours before dosing (0-hour) untilafter the 36-hour blood sample collection in each study period andreturned to the clinical facility for the 48-, 72- and 96-hour bloodsample collections. The interval between doses (0-hour) were at least 10days.

The plasma concentrations of dextromethorphan and its active metabolitedextrorphan were measured by a fully validated analytical procedure.Statistical analysis using average bioequivalence methodology wasperformed to evaluate the bioavailability of the test formulationrelative to that of the reference product for dextromethorphan anddextrorphan only.

The study was designed based on the known pharmacokinetics of NUEDEXTA®(dextromethorphan hydrobromide and quinidine sulfate) Capsules, the FDADraft Guidance on dextromethorphan hydrobromide and quinidine sulfatecapsules, and generally accepted standards for the conduct ofbioavailability/bioequivalence studies under fasted conditions andadhesion studies. To minimize any possibility of a carry-over effect, awashout period of at least 10 days was selected for this study.

The study was also designed to minimize potential drug-drug-interactionthat may affect the results of this study. For example, the subjectswere screened and monitored for taking drugs such as MAO inhibitors,tricyclic antidepressants, SSRIs, drugs that are implicated in TdP orcardiac arrhythmia, inducers or inhibitors of CYP3A4, or CYP2D6 etc.Pharmacokinetic Results

Blood samples were collected at these time points (relative to dosingminute): Pre-dose (0-hour) and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0,6.0, 7.0, 9.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 20.0, 24.0,24.5, 25.0, 26.0, 30.0, 36.0, 48.0*, 72.0* and 96.0* hours post-dose (*return sample). The samples were then processed and analyzed for bothdextromethorphan and dextrophan concentrations using validatedanalytical methods. SAS®, Version 9.4 or higher was used for allpharmacokinetic and statistical calculations.

Tables 5A-5D show the results from this study. Tables A and C show thedextromethorphan and dextrophan plasma concentrations, respectively, insubjects orally administered Neudextra (Reference) twice a day. Tables Band D show the dextromethorphan and dextrophan plasma concentrations,respectively, in subjects treated with dextromethorphan patch for 24hours.

TABLE 5A Dextromethorphan PK Profile in Subjects Treated Neudexta AUC0-t/ AUC AUC 0-t AUC Cmax Tmax Sub. Per. Seq. AUC 0-∞ 0-∞ (h · ng/mL)0-24 (ng/mL) (h) 2001 1 2 0.993 351.9471 349.606 184.0613 16.601 15 20022 1 0.964 195.315 188.2605 125.9288 10.095 18 2003 1 2 0.968 678.6678657.1278 261.3503 18.961 15 2004 2 1 0.925 1179.091 1090.282 413.96325.246 18 2005 1 2 0.985 241.7969 238.2765 139.581 10.527 16 2006 2 10.988 113.702 112.3683 71.981 5.179 18 2007 1 2 0.988 212.503 209.9133120.7003 9.266 16 2008 2 1 0.987 199.7647 197.2488 115.1745 8.949 172009 1 2 0.977 61.9881 60.5778 41.9003 3.009 17 2010 2 1 0.992 420.076416.5713 198.18 14.367 16 2011 2 1 0.991 146.6518 145.3553 94.6668 7.91216 2012 1 2 0.987 630.2464 622.358 258.1298 17.371 18 2013 2 1 0.961127.656 1082.814 391.2635 27.377 17 2014 1 2 0.99 209.3143 207.2588119.782 9.519 18 2015 2 1 0.989 203.16 200.8948 123.0515 11.967 15 20161 2 0.994 413.279 410.8915 188.3373 13.428 16 N 16 16 16 16 16 16 Mean0.98 399.0725 386.8627 178.0032 13.1109 16.625 St. Dev. 0.0182 341.34321.0667 106.3368 6.6888 1.1475 CV(%) 1.8534 85.5333 82.9924 59.738751.0169 6.902 Min. 0.9247 61.9881 60.5778 41.9003 3.009 15 Median 0.9876227.15 224.0949 132.7549 11.247 16.5 Max. 0.9942 1179.091 1090.282413.963 27.377 18 Geometric — 293.6809 287.7623 151.5212 11.4739 — MeanGeometric — 96.1162 94.5644 65.4088 60.9954 — CV(%)

TABLE 5B Dextromethorphan PK Profile in Subjects Treated DXM Patch AUC0-t/ AUC AUC AUC 0-t AUC Cmax Tmax Kel Sub. Per. Seq. 0-∞ 0-∞ (h ·ng/mL) 0-24 (ng/mL) (h) (h-1) 2001 2 2 0.995 343.5848 341.9338 225.840812.168 13 0.0521 2002 1 1 0.979 157.7533 154.4763 83.966 5.918 24 0.05982003 2 2 0.993 254.6006 252.7 138.4305 7.924 13 0.0558 2004 1 1 0.909762.9419 693.3915 227.2223 15.069 25 0.028 2005 2 2 0.981 108.1344106.0843 39.8225 3.565 24 0.0449 2006 1 1 0.976 155.7666 152.0265 76.2855.39 24 0.0406 2007 2 2 0.974 76.1848 74.1835 37.4935 2.768 24 0.06552008 1 1 0.953 160.8027 153.2865 101.7265 5.729 9 0.089 2009 2 2 0.983135.951 133.5808 60.496 5.299 24.5 0.0464 2010 1 1 0.989 170.5676168.6183 93.6805 5.488 24.5 0.0487 2011 1 1 0.981 150.6617 147.831888.5355 5.359 13 0.0594 2012 2 2 0.991 175.1153 173.5208 89.2915 5.41 240.0583 2013 1 1 0.972 135.1146 131.3655 59.5475 5.058 24.5 0.0501 2014 22 0.988 103.1524 101.9025 51.8775 3.747 13 0.0448 2015 1 1 0.99 89.527488.629 49.1685 3.503 24.5 0.0601 2016 2 2 0.98 118.201 115.859 56.22353.982 24.5 0.0418 N 16 16 16 16 16 16 16 Mean 0.9771 193.6287 186.836992.4755 6.0236 20.5313 0.0528 St. Dev. 0.0208 165.2082 149.9839 58.44793.2516 5.8807 0.0135 CV(%) 2.1321 85.3221 80.2753 63.2036 53.981528.6425 25.5494 Min. 0.9088 76.1848 74.1835 37.4935 2.768 9 0.028 Median0.9811 153.2141 149.9291 80.1255 5.3745 24 0.0511 Max. 0.9952 762.9419693.3915 227.2223 15.069 25 0.089 Geometric Mean — 160.6092 156.894279.6881 5.4375 — — Geometric CV(%) — 60.1868 58.6836 58.0178 46.2616 — —

TABLE 5C Dextrorphan PK Profile in Subjects Treated Neudexta AUC 0-t/AUC AUC AUC 0-t AUC Cmax Tmax Sub. Per. Seq. 0-∞ 0-∞ (h · ng/mL) 0-24(ng/mL) (h) 2001 1 2 0.91 54.6319 49.7395 37.0408 2.508 15 2002 2 1 0.9554.7694 52.0113 44.3253 4.736 3 2003 1 2 0.79 44.4308 35.1195 19.28231.375 3 2004 2 1 0.758 45.5979 34.5633 16.5818 0.997 18 2005 1 2 0.93349.1071 45.8165 37.2095 2.842 2 2006 2 1 0.846 21.7259 18.3733 17.47881.763 2 2007 1 2 0.923 34.5947 31.9278 25.6383 1.927 15 2008 2 1 0.86327.3844 23.634 20.3403 1.463 3 2009 1 2 0.977 61.0768 59.6648 50.62684.251 16 2010 2 1 0.88 47.2853 41.614 29.7973 2.385 5 2011 2 1 0.94444.4111 41.9088 38.2585 4.014 2 2012 1 2 0.773 35.9404 27.7748 18.53531.369 4 2013 2 1 — — 24.2913 9.816 0.709 18 2014 1 2 0.907 33.664830.522 24.7718 1.804 3 2015 2 1 0.872 42.554 37.1155 29.618 2.482 2 20161 2 0.877 37.8946 33.2445 26.2825 2.035 4 N 15 15 16 16 16 16 Mean0.8802 42.338 36.7075 27.8502 2.2913 7.1875 St. Dev. 0.0657 10.659611.2148 11.1675 1.1676 6.5138 CV(%) 7.469 25.1775 30.5518 40.098550.9602 90.6263 Min. 0.758 21.7259 18.3733 9.816 0.709 2 Median 0.880144.4111 34.8414 25.9604 1.981 3.5 Max. 0.9769 61.0768 59.6648 50.62684.736 18 Geometric Mean — 40.9614 35.0859 25.6926 2.0294 — GeometricCV(%) — 28.0586 32.3114 44.7726 55.4075 —

TABLE 5D Dextrorphan PK Profile in Subjects Treated DXM Patch AUC 0-t/AUC AUC AUC 0-t AUC Cmax Tmax Kel Sub. Per. Seq. 0-∞ 0-∞ (h · ng/mL)0-24 (ng/mL) (h) (h-1) 2001 2 2 0.816 23.5515 19.2253 9.77 0.665 260.0495 2002 1 1 — 13.3518 7.81 0.658 13 — 2003 2 2 0.786 15.0118 11.79887.563 0.478 20 0.071 2004 1 1 — — 16.3933 6.348 0.58 24.5 — 2005 2 2 — —1.5003 0 0.279 30 — 2007 2 2 — — 2.594 0.955 0.286 30 — 2008 1 1 — —7.8075 5.6295 0.431 24 — 2009 2 2 — — 4.7703 3.265 0.354 12 — 2010 1 1 —— 11.3405 6.759 0.539 26 — 2011 1 1 — — 1.6505 1.102 0.312 26 — 2012 2 2— — 4.957 2.741 0.401 24 — 2013 1 1 — — 13.1663 6.377 0.683 24 — 2014 22 — — 6.6303 4.4165 0.393 26 — 2015 1 1 — — 10.327 5.9315 0.588 14 —2016 2 2 — — 4.1193 2.386 0.319 26 — N 2 2 15 15 15 15 2 Mean 0.801119.2816 8.6421 4.7369 0.4644 23.0333 0.0602 St. Dev. 0.0215 6.03845.5101 2.8797 0.1446 5.7273 0.0152 CV(%) 2.6783 31.317 63.7586 60.792131.1453 24.8654 25.2412 Min. 0.786 15.0118 1.5003 0 0.279 12 0.0495Median 0.8011 19.2816 7.8075 5.6295 0.431 24.5 0.0602 Max. 0.816323.5515 19.2253 9.77 0.683 30 0.071 Geometric Mean — 18.8029 6.70334.1953 0.4433 — — Geometric CV(%) — 32.6691 96.3776 82.6752 32.64 — —

Based on this study, it was also unexpectedly found that for subjectstreated with DXM patch, the ratios of AUC₀₋₂₄, AUC_(0-t), and C_(max) ofDXM to DRP observed for the patch treatment were significantly higherthan the respective ratios observed for the Neudexta treatment. Forexample, the mean ratio of AUC₀₋₂₄ of DXM to DRP observed for the patchtreatment is close to 3× of that observed for Neudexta treatment(24.54:9.03), see table 6 below.

TABLE 6 Comparison of PK Profiles for Patch Neudexta Treatments NeudextaTreatment Patch Treatment AUC 0-t AUC 0-24 Cmax AUC 0-t AUC 0-24 Cmax(DXM/ (DXM/ (DXM/ (DXM/ (DXM/ (DXM/ Sub. Per. Seq. DRP) DRP) DRP) Per.Seq. DRP) DRP) DRP) 2001 1 2 7.03 4.97 6.62 2 2 17.79 23.12 18.30 2002 21 3.62 2.84 2.13 1 1 11.57 10.75 8.99 2003 1 2 18.71 13.55 13.79 2 221.42 18.30 16.58 2004 2 1 31.54 24.96 25.32 1 1 42.30 35.79 25.98 20051 2 5.20 3.75 3.70 2 2 70.71 — 12.78 2006 2 1 6.12 4.12 2.94 1 1 — — —2007 1 2 6.57 4.71 4.81 2 2 28.60 39.26 9.68 2008 2 1 8.35 5.66 6.12 1 119.63 18.07 13.29 2009 1 2 1.02 0.83 0.71 2 2 28.00 18.53 14.97 2010 2 110.01 6.65 6.02 1 1 14.87 13.86 10.18 2011 2 1 3.47 2.47 1.97 1 1 89.5780.34 17.18 2012 1 2 22.41 13.93 12.69 2 2 35.01 32.58 13.49 2013 2 144.58 39.86 38.61 1 1 9.98 9.34 7.41 2014 1 2 6.79 4.84 5.28 2 2 15.3711.75 9.53 2015 2 1 5.41 4.15 4.82 1 1 8.58 8.29 5.96 2016 1 2 12.367.17 6.60 2 2 28.13 23.56 12.48 N 16 16 16 15 16 Mean 12.07 9.03 8.8829.43 24.54 13.12 St. 11.78 10.15 9.96 22.93 18.82 5.06 Dev. CV(%)97.60% 112.45% 112.10% 77.89% 76.70% 38.60%

FIGS. 4A and 4B show the graph of dextromethorphan and dextrorphanconcentrations from 0-96 hours.

Example 5. Multilayer Patch Design

In this example, a novel multilayer design is described.

As shown in FIG. 5, an exemplary patch design useful for the embodimentsherein can include a contact layer and a reservoir layer. The contactlayer (top layer in FIG. 5) can have the following ingredients: 1) anAdhesive (e.g., DURO-TAK 287-2287): about 77.5%-about 75%; 2) Drug(Dextromethorphan base): about 10%; 3) Enhancer (e.g., IsopropylMyristate—IPM): about 10%; and 4) a Kollidon, e.g., KollidonVA64: about2.5%-about 5%. The reservoir layer can have the followingingredients: 1) an Adhesive (e.g., DURO-TAK 287-2287): about 57.5%-about20%; 2) Drug (Dextromethorphan base): about 30%-about 50%; 3) Enhancer(e.g., Isopropyl Myristate—IPM): about 10%; and 4) a Kollidon e.g.,Kollidon VA64: about 2.5%-about 20%. The bottom layer can be a backinglayer or can be an adhesive layer such as the same as the top layer.Suitable backing layers are described herein. Kollidon is a brandnamewhich refers to a vinylpyrrolidone polymer (e.g., avinylpyrrolidone-vinyl acetate copolymers, e.g., Kollidon VA64). Priorto application, the contact layer is typically protected with a releaseliner. Suitable release liners are also described herein.

In one example, the multilayer patch can have a size of 60 cm² or more,e.g., about 60 cm² to about 150 cm².

In one example, the multilayer patch can have a size of 70 cm², which isdesigned to contain a total of about 370 mg dextromethorphan base. Suchpatch is suitable for application for 7 days, which can transdermallydeliver about 20 mg or more of dextromethorphan per day for 7 days(total delivery approximately 140 mg or more) over 7 days).

Example 6. Pharmacokinetic Simulation

This example shows a simulation of Dextromethorphan (DXM or DM) andDextrorphan (DOR) Plasma Profiles over 7 days following dailyapplication of different sized patches.

The method used to simulate the plasma profile after daily dosing over 7days for patches of different sizes is called superposition. Thisinvolves repetitively adding concentration of next dose to the profileof the previous dose, without the need for any compartmental modeling,or the need to know any PK parameters. First, Dextromethorphan(abbreviated as DXM or DM) and Dextrorphan (abbreviated as DOR or DRP)mean plasma profiles after a single 24 hr application of a 70 cm² patchwas obtained with a 45 cm² patch as shown in Example 4. The assumptionsare that the absorption rate of DXM is proportionally increased withpatch size, while DXM to DRP conversion rate, DXM clearance rate, andDRP clearance rate were not changed.

Then, DXM and DRP plasma profiles from a 60 cm² and 90 cm² patch withonce-a-day application for 7 days were predicted using the predictedsingle dose profiles and the superposition principle, with theassumptions that each subsequent dosing after Day 1 will not causechanges in the clearance of DXM, DRP and conversion of DXM and DRP.

The pharmacokinetic simulation results are shown in FIGS. 6A-6D. Asshown in FIG. 6B, daily administration of a DXM patch with a size ofabout 60 cm² and above will produce a DXM plasma level falling withinthe peak and trough of the DXM concentration from oral administration ofNeudexta BID (20 mg DXM/10 mg quinidine) for 7 days. Moreover, the DXMplasma level obtained from daily administration of DXM patches are lessvariable, with the peak to trough ratio lower than those observed fromoral administration of Neudexta BID (20 mg DXM/10 mg quinidine) for 7days.

It is to be appreciated that the Detailed Description section, and notthe Summary and Abstract sections, is intended to be used to interpretthe claims. The Summary and Abstract sections may set forth one or morebut not all exemplary embodiments of the present invention ascontemplated by the inventor(s), and thus, are not intended to limit thepresent invention and the appended claims in any way.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

With respect to aspects of the invention described as a genus, allindividual species are individually considered separate aspects of theinvention. If aspects of the invention are described as “comprising” afeature, embodiments also are contemplated “consisting of or “consistingessentially of” the feature.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

All of the various aspects, embodiments, and options described hereincan be combined in any and all variations.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent that any meaning or definition of a term in this documentconflicts with any meaning or definition of the same term in a documentincorporated by reference, the meaning or definition assigned to thatterm in this document shall govern.

What is claimed is:
 1. A method of treating pseudobulbar affect in asubject in need thereof, the method comprising transdermallyadministering to the subject a therapeutically effective amount ofdextromethorphan, wherein the subject is a human subject and is notco-administered a CYP2D6 inhibitor, wherein the administering comprisesapplying a transdermal delivery device to the skin of the subject,wherein the transdermal delivery device comprises an adhesive layercomprising, by weight percentage of the adhesive layer, an adhesive inan amount of about 65% to about 85%, dextromethorphan in an amount ofabout 2% to about 12%, a permeation enhancer in an amount of about 6% toabout 12%, and optional other ingredients in an amount of about 0% toabout 20%, wherein the transdermal delivery device is a single layerdrug-in- adhesive patch, which comprises dextromethorphan dispersed inthe adhesive, and wherein the dextromethorphan in the transdermaldelivery device is in its free base form, and the transdermal deliverydevice comprises dextromethorphan as the only drug, wherein the subjectdoes not suffer from a cough or need an antitussive effect, wherein theapplying results in one or more of the following pharmacokinetic profilein the human subject: a. a mean C_(max) of dextromethorphan of about 3ng/ml to about 12 ng/ml at day 1 post application; b. a mean AUC₀₋₂₄ ofdextromethorphan of about 40 ng*h/ml to about 150 ng*h/ml at day 1 postapplication; c. a mean ratio of C_(24h)/C_(12h) of dextromethorphan ofabout 1 to about 1.5 at day 1 post application; d. a mean ratio ofC_(24h)/C_(6h) of dextromethorphan of about 1.5 to about 2.5 at day 1post application; e. a mean ratio of C_(24h)/C_(18h) of dextromethorphanof about 0.85 to about 1.3 at day 1 post application; f. a mean C_(max)of dextrorphan of not more than 2 ng/ml at day 1 post application; g. amean AUC₀₋₂₄ of dextrorphan of not more than 10 ng*h/ml at day 1 postapplication; h. a mean ratio of C_(max) of dextromethorphan to C_(max)of dextrorphan of at least about 5 at day 1 post application; and i. amean ratio of AUC₀₋₂₄ of dextromethorphan to AUC₀₋₂₄ of dextrorphan ofat least about 5 at day 1 post application.
 2. The method of claim 1,wherein the applying results in a PK profile comprising a). a meanC_(max) of dextromethorphan of about 3 ng/ml to about 12 ng/ml at day 1post application; and/or b). a mean AUC₀₋₂₄ of dextromethorphan of about40 ng*h/ml to about 150 ng*h/ml at day 1 post application.
 3. The methodof claim 2, wherein the applying results in a PK profile comprising c).a mean ratio of C_(24h)/C_(12h) of dextromethorphan of about 1 to about1.5 at day 1 post application; d). a mean ratio of C_(24h)/C_(6h) ofdextromethorphan of about 1.5 to about 2.5 at day 1 post application;and/or e). a mean ratio of C_(24h)/C_(18h) of dextromethorphan of about0.85 to about 1.3 at day 1 post application.
 4. The method of claim 2,wherein the applying results in a PK profile comprising f). a meanC_(max) of dextrorphan of not more than 2 ng/ml at day 1 postapplication; and/or g). a mean AUC₀₋₂₄ of dextrorphan of not more than10 ng*h/ml at day 1 post application.
 5. The method of claim 2, whereinthe applying results in a PK profile comprising h). a mean ratio ofC_(max) of dextromethorphan to C_(max) of dextrorphan of at least about5 at day 1 post application; and/or i). a mean ratio of AUC₀₋₂₄ ofdextromethorphan to AUC₀₋₂₄ of dextrorphan of at least about 5 at day 1post application.
 6. The method of claim 1 wherein the applying resultsin one or both of the following pharmacokinetic profile in the humansubject: a. a mean C_(max) of dextromethorphan of about 8 ng/ml to about20 ng/ml at day 7 post application; and b. a mean C_(max) of dextrorphanof not more than 2 ng/ml at day 7 post application.
 7. The method ofclaim 1, wherein the human subject is not administered any ofdesipramine, paroxetine, thioridazine, pimozide, digoxin, atazanavir,clarithromycin, indinavir, itraconazole, ketoconazole, and combinationsthereof.
 8. The method of claim 1, wherein the permeation enhancer isisopropyl myristate in an amount of about 10% of the adhesive layer. 9.The method of claim 1, wherein the transdermal delivery device isconfigured to provide dextromethorphan about 15 mg/day to about 40mg/day to the subject.
 10. The method of claim 1, wherein the subject isan extensive metabolizer of dextromethorphan.
 11. The method of claim 1,wherein the subject is a poor metabolizer of dextromethorphan.
 12. Themethod of claim 1, wherein the subject is sensitive to or otherwiseintolerant to quinidine.